Compositions, treatment systems and methods for improved cooling of lipid-rich tissue

ABSTRACT

Compositions and formulations for use with devices and systems that enable tissue cooling, such as cryotherapy applications, for alteration and reduction of adipose tissue are described. Aspects of the technology are further directed to methods, compositions and devices that provide protection of non-targeted cells (e.g., non-lipid-rich cells) from freeze damage during dermatological and related aesthetic procedures that require sustained exposure to cold temperatures. Further aspects of the technology include systems for enhancing sustained and/or replenishing release of cryoprotectant to a treatment site prior to and during cooling applications.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/934,549, filed Jan. 31, 2014, entitled “COMPOSITIONS, TREATMENTSYSTEMS AND METHODS FOR IMPROVED COOLING OF LIPID-RICH TISSUE,” U.S.Provisional Patent Application No. 61/943,250, filed Feb. 21, 2014,entitled “TREATMENT SYSTEMS, METHODS, AND APPARATUSES FOR IMPROVING THEAPPEARANCE OF SKIN;” and U.S. Provisional Patent Application No.61/943,257, filed Feb. 21, 2014, entitled “TREATMENT SYSTEMS, METHODSAND APPARATUS FOR REDUCING SKIN IRREGULARITIES CAUSED BY CELLULITE,”which are incorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE OF COMMONLY-OWNED APPLICATIONS AND PATENTS

The following commonly assigned U.S. patent applications and U.S.patents are incorporated herein by reference in their entirety:

U.S. Patent Publication No. 2008/0287839 entitled “METHOD OF ENHANCEDREMOVAL OF HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS AND TREATMENTAPPARATUS HAVING AN ACTUATOR”;

U.S. Pat. No. 6,032,675 entitled “FREEZING METHOD FOR CONTROLLED REMOVALOF FATTY TISSUE BY LIPOSUCTION”;

U.S. Patent Publication No. 2007/0255362 entitled “CRYOPROTECTANT FORUSE WITH A TREATMENT DEVICE FOR IMPROVED COOLING OF SUBCUTANEOUSLIPID-RICH CELLS”;

U.S. Pat. No. 7,854,754 entitled “COOLING DEVICE FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2011/0066216 entitled “COOLING DEVICE FORREMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2008/0077201 entitled “COOLING DEVICES WITHFLEXIBLE SENSORS”;

U.S. Patent Publication No. 2008/0077211 entitled “COOLING DEVICE HAVINGA PLURALITY OF CONTROLLABLE COOLING ELEMENTS TO PROVIDE A PREDETERMINEDCOOLING PROFILE”;

U.S. Patent Publication No. 2009/0118722, filed Oct. 31, 2007, entitled“METHOD AND APPARATUS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS ORTISSUE”;

U.S. Patent Publication No. 2009/0018624 entitled “LIMITING USE OFDISPOSABLE SYSTEM PATIENT PROTECTION DEVICES”;

U.S. Patent Publication No. 2009/0018623 entitled “SYSTEM FOR TREATINGLIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018625 entitled “MANAGING SYSTEMTEMPERATURE TO REMOVE HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018627 entitled “SECURE SYSTEM FORREMOVING HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018626 entitled “USER INTERFACES FOR ASYSTEM THAT REMOVES HEAT FROM LIPID-RICH REGIONS”;

U.S. Pat. No. 6,041,787 entitled “USE OF CRYOPROTECTIVE AGENT COMPOUNDSDURING CRYOSURGERY”;

U.S. Pat. No. 8,285,390 entitled “MONITORING THE COOLING OF SUBCUTANEOUSLIPID-RICH CELLS, SUCH AS THE COOLING OF ADIPOSE TISSUE”;

U.S. Provisional Patent Application Ser. No. 60/941,567 entitled“METHODS, APPARATUSES AND SYSTEMS FOR COOLING THE SKIN AND SUBCUTANEOUSTISSUE”;

U.S. Pat. No. 8,275,442 entitled “TREATMENT PLANNING SYSTEMS AND METHODSFOR BODY CONTOURING APPLICATIONS”;

U.S. patent application Ser. No. 12/275,002 entitled “APPARATUS WITHHYDROPHILIC RESERVOIRS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 12/275,014 entitled “APPARATUS WITHHYDROPHOBIC FILTERS FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Patent Publication No. 2010/0152824 entitled “SYSTEMS AND METHODSWITH INTERRUPT/RESUME CAPABILITIES FOR COOLING SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Pat. No. 8,192,474 entitled “TISSUE TREATMENT METHODS”;

U.S. Patent Publication No. 2010/0280582 entitled “DEVICE, SYSTEM ANDMETHOD FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2012/0022518 entitled “COMBINED MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR BODY CONTOURINGAPPLICATIONS”;

U.S. Publication No. 2011/0238050 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2011/0238051 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2012/0239123 entitled “DEVICES, APPLICATION SYSTEMSAND METHODS WITH LOCALIZED HEAT FLUX ZONES FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 13/830,413 entitled “MULTI-MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR ALTERING SUBCUTANEOUSLIPID-RICH TISSUE”; and

U.S. patent application Ser. No. 13/830,027 entitled “TREATMENT SYSTEMSWITH FLUID MIXING SYSTEMS AND FLUID-COOLED APPLICATORS AND METHODS OFUSING THE SAME”.

U.S. Patent Publication Nos. 2005/0251120 and 2008/0077211, and U.S.Pat. No. 8,285,390 are attached hereto as an Appendix, the entireties ofwhich are hereby incorporated by reference herein and made a part ofthis application.

TECHNICAL FIELD

The present disclosure relates generally to treatment devices, systems,and methods for removing heat from subcutaneous lipid-rich tissue. Inparticular, several embodiments are directed to cryoprotectantcompositions, treatment systems and methods for improved cooling oftargeted tissue.

BACKGROUND

Excess body fat, or adipose tissue, may be present in various locationsof the body, including, for example, the thigh, buttocks, abdomen,knees, back, face, arms, and other areas. Excess adipose tissue candetract from personal appearance and athletic performance. Moreover,excess adipose tissue is thought to magnify the unattractive appearanceof cellulite, which forms when subcutaneous fat lobules protrude orpenetrate into the dermis and create dimples where the skin is attachedto underlying structural fibrous strands. Cellulite and excessiveamounts of adipose tissue are often considered to be cosmeticallyunappealing. Moreover, significant health risks may be associated withhigher amounts of excess body fat.

Aesthetic improvement of the human body often involves the selectiveremoval of adipose tissue. Removal of excess adipose tissue has beenreported to have health benefits in addition to cosmetic enhancements.Currently, the most common procedures for this purpose are invasive,such as liposuction or other surgical techniques. Invasive procedures,however, tend to be associated with high cost, long recovery times, andincreased risk of complications. In many instances, non-invasive orminimally invasive procedures can allow some or all of thesedisadvantages to be avoided while providing at least comparable clinicaloutcomes as those of invasive procedures. For example, non-invasiveremoval of excess subcutaneous adipose tissue can eliminate bothunnecessary recovery time and discomfort associated with invasiveprocedures such as liposuction. Conventional non-invasive treatments forremoving excess body fat typically include topical agents, weight-lossdrugs, regular exercise, dieting, or a combination of these treatments.One drawback of these treatments is that they may not be effective oreven possible under certain circumstances. For example, when a person isphysically injured or ill, regular exercise may not be an option.Similarly, weight-loss drugs or topical agents are not an option if, asanother example, they cause an allergic or negative reaction.Furthermore, fat loss in selective areas of a person's body often cannotbe achieved using general or systemic weight-loss methods.

Other methods designed to reduce subcutaneous adipose tissue includelaser-assisted liposuction and mesotherapy. Newer non-invasive methodsinclude applying radiant energy to subcutaneous lipid-rich cells via,e.g., radio frequency and/or light energy, such as described in U.S.Patent Publication No. 2006/0036300 and U.S. Pat. No. 5,143,063, or via,e.g., high intensity focused ultrasound (HIFU) radiation such asdescribed in U.S. Pat. Nos. 7,258,674 and 7,347,855. Additional methodsand devices for non-invasively reducing subcutaneous adipose tissue bycooling are disclosed in U.S. Pat. No. 7,367,341 entitled “METHODS ANDDEVICES FOR SELECTIVE DISRUPTION OF FATTY TISSUE BY CONTROLLED COOLING”to Anderson et al. and U.S. Patent Publication No. 2005/0251120 entitled“METHODS AND DEVICES FOR DETECTION AND CONTROL OF SELECTIVE DISRUPTIONOF FATTY TISSUE BY CONTROLLED COOLING” to Anderson et al., the entiredisclosures of which are incorporated herein by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elementsor acts. The sizes and relative positions of elements in the drawingsare not necessarily drawn to scale. For example, the shapes of variouselements and angles may not be drawn to scale, and some of theseelements are arbitrarily enlarged and positioned to improve drawinglegibility. Further, the particular shapes of the elements as drawn arenot intended to convey any information regarding the actual shape of theparticular elements, and have been solely selected for ease ofrecognition in the drawings.

FIG. 1 is a partially schematic, isometric view of a treatment systemfor non-invasively removing heat from subcutaneous lipid-rich targetareas of a subject in accordance with an embodiment of the disclosure.

FIG. 2 is a partial cross-sectional view illustrating an applicatorsuitable to be used in the system of FIG. 1 in accordance withembodiments of the technology.

FIG. 3 is a partial cross-sectional view illustrating an applicatorsuitable to be used in the system of FIG. 1 in accordance with anotherembodiment of the technology.

FIG. 4 is a partial cross-sectional view illustrating an applicatorsuitable to be used in the system of FIG. 1 in accordance with a furtherembodiment of the technology.

FIG. 5 is a partial cross-sectional view illustrating the applicator ofFIG. 2 and a freezing depressant release structure suitable to be usedin the system of FIG. 1 in accordance with yet another embodiment of thetechnology.

FIG. 6 is a flow diagram illustrating a method for pre-treating a targetsite prior to cooling the target site in accordance with an embodimentof the technology.

FIG. 7 is a flow diagram illustrating another method for pre-treating atarget site using mechanical stimulation in accordance with anembodiment of the technology.

FIG. 8 is a schematic block diagram illustrating computing systemsoftware modules and subcomponents of a computing device suitable to beused in the system of FIG. 1 in accordance with an embodiment of thetechnology.

DETAILED DESCRIPTION A. Overview

The present disclosure describes cryoprotectant compositions, treatmentsystems and methods for cooling of targeted tissue. Several of thedetails set forth below are provided to describe the following examplesand methods in a manner sufficient to enable a person skilled in therelevant art to practice, make and use them. Several of the details andadvantages described below, however, may not be necessary to practicecertain examples and methods of the technology. Additionally, thetechnology may include other examples and methods that are within thescope of the technology but are not described in detail.

Reference throughout this specification to “one example,” “an example,”“one embodiment,” or “an embodiment” means that a particular feature,structure, or characteristic described in connection with the example isincluded in at least one example of the present technology. Thus, theoccurrences of the phrases “in one example,” “in an example,” “oneembodiment,” or “an embodiment” in various places throughout thisspecification are not necessarily all referring to the same example.Furthermore, the particular features, structures, routines, stages, orcharacteristics may be combined in any suitable manner in one or moreexamples of the technology. The headings provided herein are forconvenience only and are not intended to limit or interpret the scope ormeaning of the technology.

Compositions and formulations for use with devices and systems thatenable tissue cooling (e.g., for alteration and reduction of adiposetissue, body contouring and augmentation, for the treatment of acne, forthe treatment of hyperhidrosis, etc.), such as cryotherapy applications,are described. Aspects of the disclosure are further directed tomethods, compositions and devices that provide protection ofnon-targeted cells, such as non-lipid-rich cells (e.g., in the dermaland epidermal skin layers), by preventing or limiting freeze damageduring dermatological and related aesthetic procedures that requiresustained exposure to cold temperatures. For example, pretreatmentmethods and topical cryoprotectant compositions for use may improve thefreeze tolerance and/or freeze avoidance of non-lipid-rich skin cells.Further aspects of the disclosure include systems for enhancingsustained and/or replenishing release of cryoprotectant compositions toa treatment site prior to and/or during cooling applications.

Various tissue cryoprotectant compositions to reduce the susceptibilityof non-targeted skin cells exposed to cold-induced damage during heatremoval from targeted lipid-rich cells are disclosed and may include afreezing point depressant along with a thickening agent, a pH buffer, ahumectant, a surfactant and/or other adjuvants and additives tofacilitate protection of the non-lipid cells in the targeted treatmenttissue. One embodiment of a composition for use with a system forcooling subcutaneous lipid-rich cells comprises a cryoprotectantconfigured to be applied to an interface between a treatment device andskin of a human subject. Another embodiment of the compositions includescryoprotectant formulations configured to be applied topically to aregion of subject's skin prior to introduction of cooling treatment andpost-cooling applications.

Additional aspects of the technology are directed to methods fortreating a target region of a human subject's body to facilitatecryoprotectant absorption and retention in dermal and epidermal layersprior to and during the introduction of cooling. Enhanced cryoprotectantabsorption can be facilitated, for example, by increasing a temperatureof the dermal and epidermal layers prior to applying a topicalcryoprotectant and/or removing heat from lipid-rich cells in the targetregion. Further embodiments include increasing a permeability of asubject's skin to cryoprotectant compositions using mechanicalstimulation, agitation and/or abrasion.

Various aspects of the technology are directed to compositions for usewith a system for cooling subcutaneous lipid-rich tissue of a subjecthaving skin. In one embodiment, the composition can include a freezingpoint depressant (e.g., a cryoprotectant agent) configured to be appliedto the skin of the subject. The freezing point depressant can beconfigured to lower a freezing point of cells in an epidermal layerand/or a dermal layer of the skin. The composition can also include atleast one of a thickening agent, a pH buffer, a humectant and asurfactant. For example, the composition can include one or morethickening agents, one or more pH buffers, one or more humectants,and/or one or more surfactants. The composition can further include atleast one of (a) an adjuvant configured to increase permeation of thefreezing point depressant through a stratum corneum of the skin and intothe epidermis and/or dermis (e.g., epidermal and/or dermal skin layers),(b) a solute configured to increase an effective concentration of thesolute in an intracellular fluid or an extracellular fluid in theepidermis and/or dermis, (c) a hydrophilic molecule, and (d) alipophobic molecule. In one embodiment, the solute increases theeffective concentration of the freezing point depressant in theintracellular fluid in the epidermis and/or dermis. In otherembodiments, the solute increases the effective concentration of thefreezing point depressant in the extracellular fluid in the epidermisand/or dermis.

Other aspects of the technology are directed to compositions for usewith a system for transdermal cooling of targeted cells of a subjecthaving skin. In one embodiment, the composition can include a freezingpoint depressant configured to be applied to the skin of the subject.The freezing point depressant can be configured to lower a freezingpoint of non-targeted cells in a target region of the skin. Thecomposition can also include at least one of a thickening agent, a pHbuffer, a humectant and a surfactant. The composition can furtherinclude at least one of (a) an adjuvant configured to increasepermeation of the freezing point depressant through a stratum corneum ofthe skin, (b) a solute configured to increase an effective concentrationof the solute in an intracellular fluid or an extracellular fluid in thetarget region, (c) a hydrophilic molecule, and (d) a lipophobicmolecule. In some embodiments, the composition is configured to protectthe non-targeted cells while allowing targeted cells in the targetregion to be affected while cooling. In one embodiment, the targetedcells have a higher lipid content than the non-targeted cells. Forexample, the targeted cells are subcutaneous lipid-rich cells. Inanother embodiment, the targeted cells are lipid-rich cells in thebreast. For example, the cryoprotectant compositions disclosed hereincan facilitate non-target cell and mammary gland protection in thebreast while transdermal cooling can selectively target the lipid-richfat cells for breast contouring and/or breast reduction/augmentationprocedures. In a further embodiment, the targeted cells are cellsassociated with exocrine glands within or near the skin (e.g., epidermaland/or dermal layers) of a subject. For example, the targeted cells maybe lipid-producing cells residing within or at least proximate tosebaceous glands, or in another embodiment, apocrine sweat glands. Thecomposition can be in contact with at least one of the skin of a subjectat a target region and a surface of a treatment device suitable forremoving heat from the target region.

Other embodiments of the present technology include systems foraffecting lipid-rich cells in a target region of a human subject's body.In one embodiment, the system can include an applicator having aheat-exchanging element configured to reduce a temperature of the targetregion from a natural body temperature to a lower temperature in thetarget region. The system can also include a cryoprotectant releasestructure between a surface of the applicator and a skin surface in thetarget region. The cryoprotectant release structure can be configured toretain and release a cryoprotectant between the surface of theapplicator and the skin surface. In some embodiments, the system canfurther include a cryoprotectant configured to lower a freezing point ofnon-targeted cells (e.g., non-lipid-rich cells) in or near the targetregion. In one embodiment, the cryoprotectant can include one or more ofan adjuvant configured to increase absorption of the cryoprotectant intoan epidermal layer and/or dermal layer at the target region, a soluteconfigured to raise an effective concentration of the solute in theepidermal layer and/or dermal layer, a hydrophilic molecule, and alipophilic molecule.

In another embodiment, a system for non-invasive, transdermal removal ofheat from lipid-rich cells of a subject's body includes an applicatorhaving a heat-exchanging element. The heat-exchanging element can beconfigured to reduce a temperature of a target region beneath theepidermis of the subject selectively to reduce the temperature oflipid-rich cells in the target region from a natural body temperature toa lower temperature in the target region. In one embodiment, the lowertemperature can be less than −10° C., or in another embodiment betweenabout −10° C. to about −15° C., or in another embodiment between about−15° C. to about −25° C. The system can also include a firstcryoprotectant configured to lower a freezing point of non-targetedcells (e.g., non-lipid-rich cells) in or near the target region. In oneembodiment, the first cryoprotectant can be configured to lower thefreezing point of the cells to about −20° C. to about −10° C., inanother embodiment to about −18° C. to about −10° C., or in anotherembodiment to about −15° C. to about −10° C. In one embodiment, thefirst cryoprotectant can include one or more of an adjuvant configuredto increase absorption of the cryoprotectant into an epidermal layerand/or dermal layer at the target region, a solute configured to raisean effective concentration of the solute in the epidermal layer and/ordermal layer, a hydrophilic molecule, and a lipophilic molecule. Thefirst cryoprotectant, in some embodiments, protects non-lipid cells suchthat the lipid-rich cells in the target region are substantiallyaffected while non-lipid rich cells in the target region are notsubstantially affected when the temperature is reduced. In oneembodiment, the target region is subcutaneous adipose tissue. In anotherembodiment, the target region is in the dermal layer of the subject'sskin.

Additional embodiments of such systems may include a secondcryoprotectant applied to the target region. The second cryoprotectantcan be the same composition as the first cryoprotectant, or in otherembodiments, the second cryoprotectant can be different. For example,the first cryoprotectant may include alcohol (e.g., isopropyl alcohol)and the second cryoprotectant may be an alcohol-free composition. Inother embodiments, the first and second cryoprotectants are combinedinto a single composition and applied together onto the skin by rubbingthe single composition into the skin with a mild abrasive cloth. Inother embodiments, the first cryoprotectant is first applied to the skinand thereafter the second cryoprotectant is applied to the skin. Incertain embodiments, a series of substances can be applied to the targetregion. Each substance can be adapted to (1) enhance the delivery oreffect of a subsequently applied substance, (2) enhance the effect ofcryotherapy, (3) reduce treatment times, and/or (4) reduce adverseeffects of cryotherapy.

In yet another embodiment, a system for removing heat from subcutaneouslipid-rich cells of a subject having skin can include a treatment unitand an applicator having a cooling unit in communication with thetreatment unit. The system can also include a pre-treatment compositionconfigured to be applied to the skin to increase a permeability of theskin. The pre-treatment composition can, in some embodiments, comprisean alpha-hydroxy acid, glycolic acid, butylene glycol, a fatty acid,d-limonene, a terpene, a terpenoid, N-methyl-2-pyrrolidone,dimethylsulphoxide, 1,3-diphenylurea, dodecyl,N,N-dimethyl-aminoacetate,ethanol, alcohol, Azone®, Azone® derivatives, ethyl acetate,beta-cyclodextrin, alcohol, and/or isopropyl alcohol. In otherembodiments, the pre-treatment composition can be a first cryoprotectantcomposition configured to lower a freezing point of non-lipid-rich cellsat the target region. In one example, the first cryoprotectant caninclude one or more of an adjuvant configured to increase absorption ofthe first cryoprotectant into an epidermal layer and/or dermal layer atthe target region, a solute configured to raise an effectiveconcentration of the solute in the epidermal layer and/or dermal layer,a hydrophilic molecule, and a lipophilic molecule. In some embodiments,the system can further include a cryoprotectant composition, or secondcryoprotectant composition, configured to be applied to the skin topermeate into the skin to lower a freezing point of non-lipid-rich cellsin the skin. In some arrangements, the pre-treatment composition can beconfigured to facilitate an absorption of the cryoprotectant. In manyembodiments, any one of the applicator, the treatment site, thepre-treatment composition and/or the cryoprotectant can be warmed priorto contacting the skin.

Further aspects of the present technology are directed to treatmentmethods for affecting a target region of a human subject's body to altersubcutaneous adipose tissue. In one embodiment, a method can includewarming a treatment site (e.g., at or near the target region) and/orwarming an applicator, and applying a cryoprotectant to a surface of theskin at the treatment site. In another embodiment, a method can includeapplying a cryoprotectant to a surface of the skin at a treatment siteand, prior to removing heat from the treatment site, mechanicallystimulating (e.g., abrading, agitating, brushing, rubbing, massaging,etc.) an upper layer of skin at the treatment site to facilitatepenetration and/or absorption of the cryoprotectant (e.g., increase apermeability of the skin to the cryoprotectant). In either of theseembodiments, the method can also include removing heat from the targetregion of the human subject to cool subcutaneous lipid-rich cells in thetarget region to a temperature below normal body temperature. Additionalmethods for affecting a target region of a subject's body can includeapplying a cryoprotectant to a surface of the skin at a treatment siteand, prior to removing heat from the treatment site, moving thecryoprotectant along the surface of the skin at the treatment site tofacilitate absorption of the cryoprotectant.

Some of the embodiments disclosed herein can be for cosmeticallybeneficial alterations of a variety of body regions. As such, sometreatment procedures may be for the sole purpose of altering the bodyregion to conform to a cosmetically desirable look, feel, size, shape orother desirable cosmetic characteristic or feature. Accordingly, atleast some embodiments of the cosmetic procedures can be performedwithout providing any, or in another embodiment, providing minimaltherapeutic effect. For example, some treatment procedures may bedirected to treatment goals that do not include restoration of health,physical integrity, or the physical well-being of a subject. In otherembodiments, however, the cosmetically desirable treatments may havetherapeutic outcomes (whether intended or not), such as, psychologicalbenefits, alteration of body hormones levels (by the reduction ofadipose tissue), etc. The cosmetic methods can target subcutaneousregions to change a subject's appearance such as, for example,procedures performed on a subject's “love-handles” (i.e., excess adiposetissue at the side of a subject's waistline). In another embodiment, thecosmetic methods can target sebaceous glands in the subject's skin tochange a subject's appearance such as, for example, procedures performedon a subject's face. In another embodiment, the cosmetic methods cantarget sweat glands in the subject's skin to treat hyperhidrosis.

B. Cryotherapy

FIG. 1 and the following discussion provide a brief, general descriptionof an example of a suitable treatment system 100 in which aspects of thetechnology can be implemented. In some embodiments, the treatment system100 can be a temperature-controlled treatment system for exchanging heatfrom subcutaneous lipid-rich cells of a subject 101. Those skilled inthe relevant art will appreciate that other examples of the disclosurecan be practiced with other treatment systems and treatment protocols,including invasive, minimally invasive, other non-invasive medicaltreatment systems, and/or combinations of one or more of the above fortreating a subject 101. In general, the term “treatment system”, as usedgenerally herein, refers to any of the above-referenced categories ofcosmetic or medical treatment systems as well as any treatment regimensor medical device usage. In various embodiments, the treatment system100 includes a controller, a computing device, a data acquisitiondevice, a chiller, and one or more treatment devices. These componentscan be implemented in various embodiments to apply selected treatmentprofiles to the subject 101 (e.g., a human or animal) for reducingadipose tissue.

In one embodiment, the treatment system 100 is suitable for altering ahuman subject's subcutaneous adipose tissue, such as by cooling. Theterm “subcutaneous tissue” means tissue lying beneath the dermis andincludes subcutaneous fat, or adipose tissue, which primarily iscomposed of lipid-rich cells, or adipocytes. In another embodiment, thetreatment system 100 is suitable for at least partially disruptingexocrine gland function in the skin of a human subject. For example, thetreatment system 100 is suitable for altering (e.g., reducing) oraffecting sebum production, such as by cooling lipid-producing cellsresiding in or at least proximate to sebaceous glands (e.g., glandularepithelial cells) in the subject's skin. In another example, thetreatment system is suitable for altering (e.g., reducing) or affectingaxilla sweat production, such as by cooling apocrine cells residing inaxilla apocrine glands in the subject's skin. Such alteration (e.g., bycooling) is believed to be an intermediate and/or final result of one ormore mechanisms acting alone or in combination. It is thought that suchmechanism or mechanisms can trigger an apoptotic cascade, which isbelieved to be the dominant form of lipid-rich cell death bynon-invasive cooling alone or in combination with other forms of cellinterrogation.

In several embodiments, apoptosis of the subcutaneous lipid-rich cellsin the region of the subject 101 being treated is a desirable outcomefor beneficially altering (e.g., sculpting and/or reducing) adiposetissue. Apoptosis, also referred to as “programmed cell death”, is agenetically-induced death mechanism by which cells self-destruct withoutincurring damage to surrounding tissues. An ordered series ofbiochemical events may induce cells to morphologically change. Thesechanges include cellular blebbing, loss of cell membrane asymmetry andattachment, cell shrinkage, chromatin condensation, and chromosomal DNAfragmentation. Injury via an external stimulus, such as cold exposure,is one mechanism that can induce apoptosis in cells. Nagle, W. A.,Soloff, B. L., Moss, A. J. Jr., Henle, K. J. “Cultured Chinese HamsterCells Undergo Apoptosis After Exposure to Cold but NonfreezingTemperatures” Cryobiology 27, 439-451 (1990). One aspect of apoptosis,in contrast to cellular necrosis (a traumatic form of cell deathcausing, and sometimes induced by, local inflammation), is thatapoptotic cells express and display phagocytic markers on the surface ofthe cell membrane, thus marking the cells for phagocytosis by, forexample, macrophages. As a result, phagocytes can engulf and remove thedying cells (e.g., the lipid-rich cells) without eliciting an immuneresponse.

Without being bound by theory, one mechanism of apoptotic lipid-richcell death by cooling is believed to involve localized crystallizationof lipids within the adipocytes at temperatures that do not inducecrystallization in non-lipid-rich cells. The crystallized lipids mayselectively injure these cells, inducing apoptosis (and may also inducenecrotic death if the crystallized lipids damage or rupture the bilayerlipid membrane of the adipocyte). Another mechanism of injury involvesthe lipid phase transition of those lipids within the cell's bilayerlipid membrane, which results in membrane disruption, thereby inducingapoptosis. This mechanism is well documented for many cell types and maybe active when adipocytes, or lipid-rich cells, are cooled. Mazur, P.,“Cryobiology: the Freezing of Biological Systems” Science, 68: 939-949(1970); Quinn, P. J., “A Lipid Phase Separation Model of Low TemperatureDamage to Biological Membranes” Cryobiology, 22: 128-147 (1985);Rubinsky, B., “Principles of Low Temperature Preservation” Heart FailureReviews, 8, 277-284 (2003). Other possible mechanisms of adipocytedamage, described in U.S. Pat. No. 8,192,474, relates toischemia/reperfusion injury that may occur under certain conditions whensuch cells are cooled as described herein. For instance, duringtreatment by cooling as described herein, the targeted adipose tissuemay experience a restriction in blood supply and thus be starved ofoxygen due to isolation while pulled into, e.g., a vacuum cup, or simplyas a result of the cooling which may affect vasoconstriction in thecooled tissue. In addition to the ischemic damage caused by oxygenstarvation and the build-up of metabolic waste products in the tissueduring the period of restricted blood flow, restoration of blood flowafter cooling treatment may additionally produce reperfusion injury tothe adipocytes due to inflammation and oxidative damage that is known tooccur when oxygenated blood is restored to tissue that has undergone aperiod of ischemia. This type of injury may be accelerated by exposingthe adipocytes to an energy source (via, e.g., thermal, electrical,chemical, mechanical, acoustic or other means) or otherwise increasingthe blood flow rate in connection with or after cooling treatment asdescribed herein. Increasing vasoconstriction in such adipose tissue by,e.g., various mechanical means (e.g., application of pressure ormassage), chemical means or certain cooling conditions, as well as thelocal introduction of oxygen radical-forming compounds to stimulateinflammation and/or leukocyte activity in adipose tissue may alsocontribute to accelerating injury to such cells. Other yet-to-beunderstood mechanisms of injury may also exist.

In addition to the apoptotic mechanisms involved in lipid-rich celldeath, local cold exposure may induce lipolysis (i.e., fat metabolism)of lipid-rich cells. For example, cold stress has been shown to enhancerates of lipolysis from that observed under normal conditions whichserves to further increase the volumetric reduction of subcutaneouslipid-rich cells. Vallerand, A. L., Zamecnik. J., Jones, P. J. H.,Jacobs, I. “Cold Stress Increases Lipolysis, FFA Ra and TG/FFA Cyclingin Humans” Aviation, Space and Environmental Medicine 70, 42-50 (1999).

Without being bound by theory, the selective effect of cooling onlipid-rich cells is believed to result in, for example, membranedisruption, shrinkage, disabling, destroying, removing, killing, oranother method of lipid-rich cell alteration. For example, when coolingthe subcutaneous tissues to a temperature significantly lower than 37°C., subcutaneous lipid-rich cells can selectively be affected. Ingeneral, the cells in the epidermis and dermis of the subject 101 havelower amounts of lipids compared to the underlying lipid-rich cellsforming the subcutaneous tissues. Since lipid-rich cells are moresensitive to cold-induced damage than non-lipid-rich epidermal or dermalcells, it is possible to use non-invasive or minimally invasive coolingto destroy lipid-rich cells without harming the overlying skin cells.

As discussed above, deep hypodermal fat cells are more easily damaged bylow temperatures than the overlying dermal and epidermal layers of skin,and, as such, thermal conduction can be used to cool the desired layersof skin to a temperature above the freezing point of water, but belowthe freezing point of fat. However, there is an associated risk offreezing the upper layers of skin. Without being bound by theory, it isbelieved that low temperatures may potentially cause damage in theepidermis and/or dermis via at least intracellular and/or extracellularice formation. The ice may expand and rupture the cell wall, but it mayalso form sharp crystals that locally pierce the cell wall as well asvital internal organelles, either or both resulting in cell death. Whenextracellular water freezes to form ice, the remaining extracellularfluid becomes progressively more concentrated with solutes. The highsolute concentration of the extracellular fluid may cause intracellularfluid be driven through the semi-permeable cellular wall by osmosisresulting in cell dehydration and death.

A freezing point of a material is most reliably ascertained by warmingfrozen material slowly and measuring a temperature at which meltingbegins to occur. This temperature is generally not ambiguous if thematerial is slowly warmed. Partial melting will begin to occur at thefreezing/melting point. Conversely, if a non-frozen material is cooled,its freezing/melting point is harder to ascertain since it is known thatmany materials can simply “supercool,” that is they can be cooled to abulk temperature below their freezing/melting point and still remain ina non-frozen state.

In a typical procedure, a cooling element is positioned at leastproximate to the surface of a subject's skin and heat is removed fromthe underlying adipose tissue through the upper layers of the skin. Thiscreates a thermal gradient with the coldest temperatures near thecooling element (e.g., the upper layers of skin). When cooling isapplied to the skin, for example, the resulting thermal gradient causesthe temperature of the upper layer(s) of the skin to be lower than thatof the targeted underlying lipid-rich cells. This makes it challengingto reduce the temperature of the deep lipid-rich cells low enough to bedestructive to these target cells (e.g., induce apoptosis, cell death,etc.) while also maintaining the temperature of the upper and surfaceskin cells high enough so as to be protective (e.g., non-destructive).The temperature difference between these two thresholds can be small(e.g., approximately, 5° C. to about 10° C., less than 10° C., less than15° C., etc.). Protection of the overlying non-lipid-rich cells (e.g.,typically water-rich dermal and epidermal skin cells) from freeze damageduring dermatological and related aesthetic procedures that requiresustained exposure to cold temperatures may include improving the freezetolerance and/or freeze avoidance of these skin cells.

In some embodiments, the treatment system 100 can cool the skin of thepatient to a temperature in a range of from about −20° C. to about 20°C. In other embodiments, the cooling temperatures can be from about −20°C. to about 10° C., from about −18° C. to about 5° C., from about −15°C. to about 5° C., or from about −15° C. to about 0° C. In furtherembodiments, the cooling temperatures can be less than −10° C., or inyet another embodiment, from about −15° C. to about −25° C.

As explained in more detail below, a cryoprotectant having a freezingpoint in the range of about −40° C. to about 0° C. can be applied to thesurface of the skin of the patient or subject 101, or to an interfacebetween the treatment device or applicator 104 and the skin of thepatient or subject 101. As used herein, “cryoprotectant,”“cryoprotectant agent,” and “composition” mean substances (e.g.,compositions, formulations, compounds, etc.) that assist in preventingfreezing of non-lipid-rich tissue (e.g., dermal and/or epidermal tissue)compared to an absence of the substances(s). In one embodiment, thecryoprotectant allows, for example, the treatment device or applicator104 to be pre-cooled prior to being applied to the subject 101 for moreefficient treatment. In another embodiment, the cryoprotectant allowsfor enhanced uptake or absorption and/or retention in the dermal andepidermal layers prior to and during the introduction of cooling.Further, the cryoprotectant can also enable the treatment device orapplicator 104 to be maintained at a desired temperature whilepreventing ice from forming on a surface of the treatment device orapplicator 104, and thus reduces the delay in reapplying the treatmentdevice or applicator 104 to the subject. Yet another aspect of thetechnology is that the cryoprotectant may prevent the treatment deviceor applicator 104 from freezing to the skin of the patient or subject101. Additionally, the cryoprotectant may protect biological tissues ofa subject, such as a mammal, from freezing damage (e.g., damage due toice formation). The cryoprotectant composition may also include one ormore additives present in the compound and configured to provideselected properties to the compound. Further details regardingcryoprotectants suitable for use with the treatment system 100 and/or intreatment regimens associated with cooling lipid-rich tissue aredescribed in greater detail below.

C. Suitable Cryoprotectant and Pre-Treatment Compositions

A cryoprotectant suitable to be used in the treatment system 100 of FIG.1 and/or in treatment regimens associated with use of suitable treatmentsystems for cooling lipid-rich or lipid-producing tissue (e.g.,subcutaneous adipose tissue, glandular epithelial cells) is a substancethat may protect biological tissues of a subject from freezing damage(e.g., damage due to ice formation within the tissue). Thecryoprotectant can be used as a pre-treatment formulation applied to theskin of the subject prior to removing heat to increase a permeability ofthe skin and/or to lower a freezing point of non-lipid or otherwisenon-targeted cells (e.g., in epidermal and/or dermal layers). In theseor other embodiments, the cryoprotectant can also be used during heatremoval when provided with the applicator 104 (FIG. 1) and as furtherdescribed herein.

The cryoprotectant may contain a freezing point depressant along withone or more other components, e.g., a thickening agent, a pH buffer, ahumectant, a surfactant, and/or other additives configured to provideselected properties to the compound. The cryoprotectant may beformulated as a non-freezing liquid (e.g., an aqueous solution or anon-aqueous solution), a non-freezing gel, a non-freezing hydrogel, or anon-freezing paste. The cryoprotectant may be hygroscopic, thermallyconductive, and can be biocompatible. In certain embodiments, thecryoprotectant may be formulated to be acoustically transparent to allowultrasound to pass through the cryoprotectant, such as a water-based geldescribed in U.S. Pat. No. 4,002,221 issued to Buchalter and U.S. Pat.No. 4,459,854 issued to Richardson et al., the entire disclosures ofwhich are incorporated herein by reference.

The freezing point depressant can include propylene glycol (PG),polyethylene glycol (PEG), polypropylene glycol (PPG), ethylene glycol,dimethyl sulfoxide (DMSO), combinations thereof, or other glycols. Thefreezing point depressant may also include ethanol, propanol,iso-propanol, butanol, and/or other suitable alcohol compounds. Certainfreezing point depressants (e.g., PG, PPG, PEG, etc.) may also be usedto improve spreadability of the cryoprotectant and to providelubrication. The freezing point depressant may lower the freezing pointof a solution (e.g., body fluid) to about 0° C. to −40° C. In otherembodiments the freezing point of a solution can be lowered to about−10° C. to about −20° C., about −10° C. to about −18° C., or to about−10° C. to about −15° C. In certain embodiments, the freezing point of asolution can be lowered to a temperature less than about 0° C., lessthan about −5° C., less than about −10° C., less than about −12° C.,less than about −15° C., less than about −16° C., less than about −17°C., less than about −18° C., less than about −19° C., or less than about−20° C. For example, the freezing point depressant may lower thefreezing point of a solution (e.g., body fluid) to a temperature lessthan about −20° C. to about −25° C., less than about −20° C. to about−30° C., less than about −25 to about −35° C., or less than about −30°C. to about −40° C.

The thickening agent can include carboxyl polyethylene polymer,hydroxyethyl xylose polymer, carboxyl methylcellulose, hydroxyethylcellulose (HEC), and/or other viscosity modifiers to provide a viscosityin the range of about 1 cP to about 10,000 cP. In one embodiment, thethickening agent can provide a viscosity in the range of about 4,000 cPto about 8,000 cP. In another embodiment, the thickening agent canprovide a viscosity in the range of about 5,000 cP to about 7,000 cP.Other viscosities can be achieved, if needed or desired. In variousembodiments, a cryoprotectant having a viscosity in one or more of theseranges may readily adhere to the treatment device, the skin of thesubject, and/or the interface between the treatment device and the skinof the subject during treatment.

The pH buffer may include cholamine chloride, cetamide, glycine,tricine, glycinamide, bicine, and/or other suitable pH buffers. The pHbuffer may help the cryoprotectant to have a consistent pH of about 3.5to about 11.5. In other embodiments, the pH can be consistently betweenabout 5 to about 9.5, and in further embodiments between about 6 toabout 7.5. In certain embodiments, the pH of the cryoprotectant may beclose to the pH of the skin of the subject.

The humectant may include glycerin, alkylene glycol, polyalkyleneglycol, propylene glycol, glyceryl triacetate, polyols (e.g., sorbitoland/or maltitol), polymeric polyols (e.g., polydextrose), quillaia,lactic acid, and/or urea. The humectant may promote the retention ofwater to prevent the cryoprotectant from drying out.

The surfactant may include sodium dodecyl sulfate, ammonium laurylsulfate, sodium lauryl sulfate, alkyl benzene sulfonate, sodium laurylether sulfate, and other suitable surfactants. The surfactant maypromote easy spreading of the cryoprotectant when an operator appliesthe cryoprotectant to the treatment device, the skin of the subject,and/or the interface between the treatment device and the skin of thesubject during treatment.

In several embodiments, the cryoprotectant composition may also includeadjuvants that increase the concentration of the cryoprotectant at lowertissue depths. Such adjuvants can include, for example, glycolic acidand/or other alpha-hydroxy acids, such as lactic acid, citric acid,mandelic acid, alcohol, and/or isopropyl alcohol. In some embodiments,such adjuvants can induce diminished cohesion between corneocytes at thelowest levels of the stratum corneum allowing facilitated permeation ofthe cryoprotectant formulation into the epidermis and dermis. In oneembodiment, glycolic acid can facilitate cryoprotection ofmucopolysaccharides present in the extracellular matrix of the epidermaland dermal tissue layers.

The cryoprotectant composition may also include solutes and/or adjuvantsthat locally modify colligative properties of the tissue to, forexample, depress the freezing point of the non-lipid-rich cells affectedby the cryoprotectant. Freezing point depression describes a process inwhich adding a solute or increasing the effective concentration of asolute in the intracellular fluid compartment of the non-lipid-richcells or in the extracellular fluid surrounding the non-lipid-richcells, decreases the freezing point of the respective fluids. Some suchsolutes and/or adjuvants can include, for example, calcium salts (e.g.,calcium chloride), potassium salts (e.g., potassium chloride, potassiumacetate), magnesium salts (e.g., magnesium chloride), ammonium sulphate,acetic acid, glucose, urea, camphor, menthyl lactate, mannose, andrelated compounds.

In some compositions, addition or an increase in concentration ofsolutes in the cryoprotectant can be used to form a hypertonicformulation that locally dehydrates non-lipid-rich tissue (e.g., viaosmotic dehydration). For example, the composition can include sodiumsalts (e.g., sodium chloride), calcium salts (e.g., calcium chloride),potassium salts (e.g., potassium chloride, potassium acetate), magnesiumsalts (e.g., magnesium chloride), ammonium sulphate and relatedcompounds.

In further embodiments, the cryoprotectant compositions can includehydrophilic and/or lipophobic molecules that favorably partition thecryoprotectant within the upper layers (e.g., the epidermis and dermis)of the skin. Examples of hydrophilic molecules can include manycompounds, especially those that reduce the surface tension of water,such as surfactants, gelatins and hydrogels. In one embodiment, thecryoprotectant includes glycolic acid that is completely miscible inwater and is hydrophilic. Examples of lipophobic molecules can includefluorocarbons, which are typically non-polar and immiscible in water.

The cryoprotectant may also include other additives in addition to or inlieu of the composition components described above. For example, some ofthe embodiments of cryoprotectant compositions may also include acoloring agent, fragrance or perfume, emulsifier, stabilizer, ananesthetic agent, and/or other ingredient.

In a particular embodiment, the cryoprotectant may include about 30%propylene glycol, about 30% glycerin, and about 40% ethanol by weight.In another embodiment, the cryoprotectant may include about 40%propylene glycol, about 0.8% hydroxyethyl cellulose, and about 59.2%water by weight. In a further embodiment, the cryoprotectant may includeabout 50% polypropylene glycol, about 40% glycerin, and about 10%ethanol by weight. In yet another embodiment, the cryoprotectant mayinclude about 59.5% water, about 40% propylene, and about 0.5%hydroxyethyl cellulose by weight.

In other embodiments, the cryoprotectant can include about 30-40%propylene glycol or polypropylene glycol. In one embodiment, thecryoprotectant can include about 30-50% by volume of one or morefreezing point depressants. Some cryoprotectant compositions can furtherinclude 50% wt./vol. to about 70% wt./vol. of a combination of one ormore of a thickening agent, a pH buffer, a humectant, a surfactant, andone more additives that (a) facilitate permeation of the cryoprotectantinto the epidermis and dermis, (b) increase an intracellularconcentration of solutes of dermal and epidermal cells, (c) form ahypertonic cryoprotectant formulation and/or (d) hydrophilic and/orlipophobic molecules.

In further embodiments, the cryoprotectant composition can include oneor more freezing point depressants in an amount between about 25%wt./vol. and about 55% wt. vol., about 30% wt./vol. and about 50%wt./vol., about 30% wt./vol. and about 40% wt./vol., about 35% wt./vol.and about 48% wt./vol. about 35% wt./vol. and about 45% wt./vol., about38% wt./vol. and about 42% wt./vol. about 40% wt./vol. and about 50%wt./vol., about 40% wt./vol. and about 45% wt./vol.; or, in otherembodiments, greater than about 30% wt./vol., about 35% wt./vol., about40% wt./vol., about 45% wt./vol., or about 50% wt./vol.

In a particular embodiment, a first cryoprotectant composition for useas a pre-treatment formulation (e.g., for affecting skin at thetreatment site prior to the removal of heat), can include about 30%wt./vol. isopropyl alcohol, about 40% propylene glycol, and about 30%water. A second cryoprotectant composition for use during heat removal(e.g., cooling and/or at least partially or totally freezing of targetedtissue) can be the same formulation as the first cryoprotectantcomposition or can be different. For example, the second cryoprotectantcan comprise about 40% propylene glycol and about 60% water.

In other embodiments, the cryoprotectant composition (e.g., first and/orsecond cryoprotectant compositions) can include a combination of one ormore of a thickening agent, a pH buffer, a humectant, a surfactant, andone more additives that (a) facilitate permeation of the cryoprotectantinto the epidermis and dermis, (b) increase an intracellularconcentration of solutes of dermal and epidermal cells, (c) form ahypertonic cryoprotectant formulation and/or (d) hydrophilic and/orlipophobic molecules in an amount totaling between about 45% wt./vol.and about 75% wt. vol., about 50% wt./vol. and about 70% wt./vol., about60% wt./vol. and about 70% wt./vol., about 52% wt./vol. and about 65%wt./vol. about 55% wt./vol. and about 65% wt./vol., about 58% wt./vol.and about 62% wt./vol. about 50% wt./vol. and about 60% wt./vol., about55% wt./vol. and about 60% wt./vol.

One aspect of the present technology described above is that an operatormay use lower treatment temperatures for selectively affectinglipid-rich cells of the subject without causing freezing damage to thenon-lipid-rich cells in the epidermis and/or dermis of the subject. Theapplied cryoprotectant may lower the freezing point of the skin of thesubject or body fluid in the target region to at least reduce the riskof intracellular and/or extracellular ice formation at such lowtreatment temperatures.

Another aspect of the present technology is that the non-lipid-richcells in the epidermis and/or dermis of the patient may be continuallyprotected against freezing damage. It is believed that a topicallyadministered cryoprotectant may protect the treatment region of the skinof the subject. After the cryoprotectant is applied to the skin of thesubject, the cryoprotectant is believed to enter the epidermis, thedermis, and eventually the blood stream of the subject. The subject'sblood stream then may carry the cryoprotectant away from the treatmentregion. As a result, the cryoprotectant concentration in the treatmentregion drops, and the freezing point of the subject's affected bodyfluid increases to heighten the risk of freezing damage. Accordingly,continually supplying the cryoprotectant to the skin of the subject mayat least reduce or even prevent such a risk. Further, topicallyadministering, either before heat removal as a pre-treatment compositionor in conjunction with the applicator 104 (FIG. 1) during heat removal,a cryoprotectant that is effectively partitioned in the epidermis and/ordermis of the subject may prevent the cryoprotectant from being carriedby the blood stream away from the treatment site during treatment. Insome embodiments, a sufficient amount of cryoprotectant can becontinuously or periodically delivered to the non-targeted tissue toprevent or inhibit freezing damage to the non-targeted tissue.

Still another aspect associated with several of the embodimentsdescribed above is that the additives, adjuvants, solutes, etc. in thecryoprotectant can provide a variety of desired additional properties tothe cryoprotectant material, with minimal or no effect on the chemistryand rheological properties of the cryoprotectant. Accordingly, theadditives will not interfere with the ability of the cryoprotectant toprotect a subject's biological tissues from freezing. Further, variousadditives described herein will enhance and/or facilitate the ability ofthe cryoprotectant to protect a subject's biological tissues fromfreezing or other types of damage.

As described herein, the cryoprotectant can be used with the treatmentsystem 100 to transdermally cool and selectively affect the patient'ssubcutaneous lipid-rich tissue while protecting non-lipid rich cells(e.g., residing in epidermal and/or dermal layers) from beingsubstantially affected at the reduced temperatures. Subcutaneouslipid-rich tissue can be treated for a variety of therapeutic andcosmetic body-contouring applications, such as reduction of adiposetissue residing in identified portions of the patient's body, such aschin, cheeks, arms, pectoral areas, thighs, calves, buttocks, abdomen,“love handles”, back, breast, etc. For example, use of thecryoprotectant with the treatment system 100 to transdermally cooladipose tissue in the breast can be used for breast contouring and sizereduction in a manner that facilitates protection of non-target tissuein the breast. Further examples include use of the cryoprotectant andtreatment system 100 to contour and/or reduce a volumetric size of lovehandles, abdominal fat, back fat, etc., without substantially affectingnon-targeted cells (e.g., cells in the epidermal and/or dermal layers).

In another embodiment, the cryoprotectant can be used with the treatmentsystem 100 to cool the skin of the patient to selectively affect (e.g.,injure, damage, kill) secreting exocrine glandular cells. For example,secreting glandular cells residing in axilla apocrine sweat glands canbe targeted by the treatment system 100 for the treatment ofhyperhidrosis. In another example, lipid-producing cells residing in orat least proximate to sebaceous glands (e.g., glandular epithelialcells) present in the dermis of a target region can be targeted by thetreatment system 100 for the treatment of acne or other skin condition.The lipid-producing cells residing in and/or proximate to sebaceousglands contribute to production of sebum, a waxy and oily secretion thatcan contribute to acne. For example, the treatment system 100 can beconfigured to reduce a temperature of a dermal layer of skin to reducethe temperature of lipid-producing cells residing in or at leastproximate to sebaceous glands such that the targeted lipid-producingcells excrete a lower amount of sebum, such that there are fewerlipid-producing cells resulting in less sebum production within thetargeted sebaceous glands, or in another embodiment, such that thesebaceous glands are destroyed. The treatment system 100 can beconfigured, for example, to reduce a subject's acne by coolingacne-prone regions of the body, such as the face, back, shoulders andchest.

D. Suitable Treatment System

Referring to FIG. 1, the illustration is a partially schematic,isometric view showing one example of the treatment system 100 fornon-invasively removing heat from subcutaneous lipid-rich target areasof the patient or subject 101, such as an abdominal area 102 or anothersuitable area. The applicator 104 can engage the target area of thesubject 101 and a treatment unit 106 that operate together to cool orotherwise remove heat from the subcutaneous lipid-rich cells of thesubject 101. The applicator 104 can be part of an application system,and the applicator 104 can have various configurations, shapes and sizessuitable for different body parts such that heat can be removed from anycutaneous or subcutaneous lipid-rich target area of the subject 101. Forexample, various types of applicators may be applied during treatment,such as a vacuum applicator, a belt applicator (either of which may beused in combination with a massage or vibrating capability), and soforth. Each applicator 104 may be designed to treat identified portionsof the patient's body, such as chin, cheeks, arms, pectoral areas,thighs, calves, buttocks, abdomen, “love handles”, back, breast, and soforth. For example, the vacuum applicator may be applied at the backregion, and the belt applicator can be applied around the thigh region,either with or without massage or vibration. Exemplary applicators andtheir configurations usable or adaptable for use with the treatmentsystem 100 variously are described in, e.g., commonly assigned U.S. Pat.No. 7,854,754 and U.S. Patent Publication Nos. 2008/0077201,2008/0077211 and 2008/0287839. In further embodiments, the system 100may also include a patient protection device (not shown) incorporatedinto or configured for use with the applicator 104 that prevents theapplicator from directly contacting a patient's skin and therebyreducing the likelihood of cross-contamination between patients,minimizing cleaning requirements for the applicator. The patientprotection device may also include or incorporate various storage,computing, and communications devices, such as a radio frequencyidentification (RFID) component, allowing for example, use to bemonitored and/or metered. Exemplary patient protection devices aredescribed in commonly assigned U.S. Patent Publication No. 2008/0077201.

In the present example, the system 100 can also include the treatmentunit 106 and supply and return fluid lines 108 a-b between theapplicator 104 and the treatment unit 106. A treatment unit 106 is adevice that can increase or decrease the temperature at a connectedapplicator 104 that is configured to engage the subject and/or thetarget region of the subject. The treatment unit 106 can remove heatfrom a circulating coolant to a heat sink and provide a chilled coolantto the applicator 104 via the fluid lines 108 a-b. Alternatively, thetreatment unit 106 can circulate warm coolant to the applicator 104during periods of warming. In further embodiments, the treatment unit106 can circulate coolant through the applicator 104 and increase ordecrease the temperature of the applicator by controlling power deliveryto one or more Peltier-type thermoelectric elements incorporated withinthe applicator. Examples of the circulating coolant include water,glycol, synthetic heat transfer fluid, oil, a refrigerant, and/or anyother suitable heat conducting fluid. The fluid lines 108 a-b can behoses or other conduits constructed from polyethylene, polyvinylchloride, polyurethane, and/or other materials that can accommodate theparticular circulating coolant. The treatment unit 106 can be arefrigeration unit, a cooling tower, a thermoelectric chiller, or anyother device capable of removing heat from a coolant. In one embodiment,the treatment unit 106 can include a fluid chamber 105 configured tohouse and provide the coolant. Alternatively, a municipal water supply(e.g., tap water) can be used in place of or in conjunction with thetreatment unit 106. In a further embodiment, the applicator 104 can be afluid-cooled applicator capable of achieving a desired temperatureprofile such as those described in U.S. patent application Ser. No.13/830,027, incorporated herein by reference in its entirety. Oneskilled in the art will recognize that there are a number of othercooling technologies that could be used such that the treatment unit,chiller, and/or applicator need not be limited to those describedherein.

The system 100 can optionally include an energy-generating unit 107 forapplying energy to the target region, for example, to furtherinterrogate cooled lipid-rich cells in cutaneous or subcutaneous layersvia power-lines 109 a-b between the applicator 104 and theenergy-generating unit 107. In one embodiment, the energy-generatingunit 107 can be an electroporation pulse generator, such as a highvoltage or low voltage pulse generator, capable of generating anddelivering a high or low voltage current, respectively, through thepower lines 109 a, 109 b to one or more electrodes (e.g., cathode,anode) in the applicator 104. In other embodiments, theenergy-generating unit 107 can include a variable powered RF generatorcapable of generating and delivering RF energy, such as RF pulses,through the power lines 109 a, 109 b or to other power lines (notshown). In a further embodiment, the energy-generating unit 107 caninclude a microwave pulse generator, an ultrasound pulse lasergenerator, or high frequency ultrasound (HIFU) phased signal generator,or other energy generator suitable for applying energy, for example, tofurther interrogate cooled lipid-rich cells in cutaneous or subcutaneouslayers. In some embodiments (e.g., RF return electrode, voltage returnwhen using a monopolar configuration, etc.), the system 100 can includea return electrode 111 located separately from the applicator 104; powerline 109 c (shown in dotted line) can electrically connect the returnelectrode 111, if present, and the energy-generating unit 107. Inadditional embodiments, the system 100 can include more than one energygenerator unit 107 such as any one of a combination of the energymodality generating units described herein. Systems havingenergy-generating units and applicators having one or more electrodesare described in commonly assigned U.S. Patent Publication No.2012/0022518 and U.S. patent application Ser. No. 13/830,413.

In the illustrated example, the applicator 104 is associated with atleast one treatment unit 106. The applicator 104 can provide mechanicalenergy to create a vibratory, massage, and/or pulsatile effect. Theapplicator 104 can include one or more actuators, such as, motors witheccentric weight, or other vibratory motors such as hydraulic motors,electric motors, pneumatic motors, solenoids, other mechanical motors,piezoelectric shakers, and so on, to provide vibratory energy or othermechanical energy to the treatment site. Further examples include aplurality of actuators for use in connection with a single applicator104 in any desired combination. For example, an eccentric weightactuator can be associated with one section of an applicator 104, whilea pneumatic motor can be associated with another section of the sameapplicator 104. This, for example, would give the operator of thetreatment system 100 options for differential treatment of lipid-richcells within a single region or among multiple regions of the subject101. The use of one or more actuators and actuator types in variouscombinations and configurations with an applicator 104 may be possible.

The applicator 104 can include one or more heat-exchanging units. Eachheat-exchanging unit can include or be associated with one or morePeltier-type thermoelectric elements, and the applicator 104 can havemultiple individually controlled heat-exchanging zones (e.g., between 1and 50, between 10 and 45; between 15 and 21, approximately 100, etc.)to create a custom spatial cooling profile and/or a time-varying coolingprofile. Each custom treatment profile can include one or more segments,and each segment can include a specified duration, a target temperature,and control parameters for features such as vibration, massage, vacuum,and other treatment modes. Applicators having multiple individuallycontrolled heat-exchanging units are described in commonly assigned U.S.Patent Publication Nos. 2008/0077211 and 2011/0238051.

The system 100 can further include a power supply 110 and a controller114 operatively coupled to the applicator 104. In one embodiment, thepower supply 110 can provide a direct current voltage to the applicator104 to remove heat from the subject 101. The controller 114 can monitorprocess parameters via sensors (not shown) placed proximate to theapplicator 104 via a control line 116 to, among other things, adjust theheat removal rate and/or energy delivery rate based on the processparameters. The controller 114 can further monitor process parameters toadjust the applicator 104 based on treatment parameters, such astreatment parameters defined in a custom treatment profile orpatient-specific treatment plan, such as those described, for example,in commonly assigned U.S. Pat. No. 8,275,442.

The controller 114 can exchange data with the applicator 104 via anelectrical line 112 or, alternatively, via a wireless or an opticalcommunication link. Note that control line 116 and electrical line 112are shown in FIG. 1 without any support structure. Alternatively,control line 116 and electrical line 112 (and other lines including, butnot limited to fluid lines 108 a-b and power lines 109 a-b) may bebundled into or otherwise accompanied by a conduit or the like toprotect such lines, enhance ergonomic comfort, minimize unwanted motion(and thus potential inefficient removal of heat from and/or delivery ofenergy to subject 101), and to provide an aesthetic appearance to thesystem 100. Examples of such a conduit include a flexible polymeric,fabric, or composite sheath, an adjustable arm, etc. Such a conduit (notshown) may be designed (via adjustable joints, etc.) to “set” theconduit in place for the treatment of the subject 101.

The controller 114 can include any processor, Programmable LogicController, Distributed Control System, secure processor, and the like.A secure processor can be implemented as an integrated circuit withaccess-controlled physical interfaces; tamper resistant containment;means of detecting and responding to physical tampering; secure storage;and shielded execution of computer-executable instructions. Some secureprocessors also provide cryptographic accelerator circuitry. Securestorage may also be implemented as a secure flash memory, secure serialEEPROM, secure field programmable gate array, or secureapplication-specific integrated circuit.

In another aspect, the controller 114 can receive data from an inputdevice 118 (shown as a touch screen), transmit data to an output device120, and/or exchange data with a control panel (not shown). The inputdevice 118 can include a keyboard, a mouse, a stylus, a touch screen, apush button, a switch, a potentiometer, a scanner, an audio componentsuch as a microphone, or any other device suitable for accepting userinput. The output device 120 can include a display or touch screen, aprinter, video monitor, a medium reader, an audio device such as aspeaker, any combination thereof, and any other device or devicessuitable for providing user feedback.

In the embodiment of FIG. 1, the output device 120 is a touch screenthat functions as both an input device 118 and an output device 120. Thecontrol panel can include visual indicator devices or controls (e.g.,indicator lights, numerical displays, etc.) and/or audio indicatordevices or controls. The control panel may be a component separate fromthe input device 118 and/or output device 120, may be integrated withone or more of the devices, may be partially integrated with one or moreof the devices, may be in another location, and so on. In alternativeexamples, the control panel, input device 118, output device 120, orparts thereof (described herein) may be contained in, attached to, orintegrated with the applicator 104. In this example, the controller 114,power supply 110, control panel, treatment unit 106, input device 118,and output device 120 are carried by a rack 124 with wheels 126 forportability. In alternative embodiments, the controller 114 can becontained in, attached to, or integrated with the multi-modalityapplicator 104 and/or the patient protection device described above. Inyet other embodiments, the various components can be fixedly installedat a treatment site. Further details with respect to components and/oroperation of applicators 104, treatment units 106, and other componentsmay be found in commonly-assigned U.S. Patent Publication No.2008/0287839.

In operation, and upon receiving input to start a treatment protocol,the controller 114 can cause one or more power supplies 110, one or moretreatment units 106, and one or more applicators 104 to cycle througheach segment of a prescribed treatment plan. In so doing, power supply110 and treatment unit 106 provide coolant and power to one or morefunctional components of the applicator 104, such as thermoelectriccoolers (e.g., TEC “zones”), to begin a cooling cycle and, for example,activate features or modes such as vibration, massage, vacuum, etc.

Using temperature sensors (not shown) proximate to the one or moreapplicators 104, the patient's skin, a patient protection device, orother locations or combinations thereof, the controller 114 candetermine whether a temperature or heat flux is sufficiently close tothe target temperature or heat flux. It will be appreciated that while aregion of the body (e.g., adipose tissue) has been cooled or heated tothe target temperature, in actuality that region of the body may beclose but not equal to the target temperature, e.g., because of thebody's natural heating and cooling variations. Thus, although the systemmay attempt to heat or cool the tissue to the target temperature or toprovide a target heat flux, a sensor may measure a sufficiently closetemperature or heat flux. If the target temperature has not beenreached, power can be increased or decreased to change heat flux tomaintain the target temperature or “set-point” selectively to affectlipid-rich subcutaneous adipose tissue.

When the prescribed segment duration expires, the controller 114 mayapply the temperature and duration indicated in the next treatmentprofile segment. In some embodiments, temperature can be controlledusing a variable other than or in addition to power.

In some embodiments, heat flux measurements can indicate other changesor anomalies that can occur during treatment administration. Forexample, an increase in temperature detected by a heat flux sensor canindicate a freezing event at the skin or underlying tissue (i.e., dermaltissue). An increase in temperature as detected by the heat flux sensorscan also indicate movement associated with the applicator, causing theapplicator to contact a warmer area of the skin, for example. Methodsand systems for collection of feedback data and monitoring oftemperature measurements are described in commonly assigned U.S. Pat.No. 8,285,390.

The applicators 104 may also include additional sensors to detectprocess treatment feedback. Additional sensors may be included formeasuring tissue impedance, treatment application force, tissue contactwith the applicator and energy interaction with the skin of the subject101 among other process parameters.

In one embodiment, feedback data associated heat removal from lipid-richcells in the cutaneous or subcutaneous layer can be collected inreal-time. Real-time collection and processing of such feedback data canbe used in concert with treatment administration to ensure that theprocess parameters used to alter or reduce subcutaneous adipose tissueare administered correctly and efficaciously.

Examples of the system 100 may provide the applicator 104 which damages,injures, disrupts or otherwise reduces lipid-rich cells generallywithout collateral damage to non-lipid-rich cells in the treatmentregion. In general, it is believed that lipid-rich cells selectively canbe affected (e.g., damaged, injured, or disrupted) by exposing suchcells to low temperatures that do not so affect non-lipid-rich cells.Moreover, as discussed above, a cryoprotectant can be administeredtopically to the skin of the subject 101 at the treatment site and/orused with the applicator 104 to, among other advantages, assist inpreventing freezing of the non-lipid-rich tissue (e.g., in the dermaland epidermal skin layers) during treatment to selectively interrogatelipid-rich cells in the treatment region so as to beneficially andcosmetically alter subcutaneous adipose tissue, treat sweat glands,and/or reduce sebum secretion. As a result, lipid-rich cells, such assubcutaneous adipose tissue and glandular epithelial cells, can bedamaged while other non-lipid-rich cells (e.g., dermal and epidermalskin cells) in the same region are generally not damaged even though thenon-lipid-rich cells at the surface may be subject to even lowertemperatures. In some embodiment, the mechanical energy provided by theapplicator 104 may further enhance the effect on lipid-rich cells bymechanically disrupting the affected lipid-rich cells. In one mode ofoperation, the applicator 104 may be configured to be a handheld devicesuch as the device disclosed in commonly-assigned U.S. Pat. No.7,854,754.

Applying the applicator 104 with pressure or with a vacuum type force tothe subject's skin or pressing against the skin can be advantageous toachieve efficient treatment. In general, the subject 101 has an internalbody temperature of about 37° C., and the blood circulation is onemechanism for maintaining a constant body temperature. As a result,blood flow through the skin and subcutaneous layer of the region to betreated can be viewed as a heat source that counteracts the cooling ofthe subdermal fat. As such, cooling the tissue of interest requires notonly removing the heat from such tissue but also that of the bloodcirculating through this tissue. Thus, temporarily reducing oreliminating blood flow through the treatment region, by means such as,e.g., applying the applicator with pressure, can improve the efficiencyof tissue cooling and avoid excessive heat loss through the dermis andepidermis. Additionally, a vacuum can pull skin away from the body whichcan assist in cooling targeted underlying tissue.

FIG. 2 is a schematic, cross-sectional view illustrating a treatmentdevice or applicator 200 for non-invasively removing heat fromsubcutaneous lipid-rich target areas of the subject 101 (FIG. 1) inaccordance with an embodiment of the present technology. The applicator200 can include a heat-exchanging unit (e.g., a cooling unit), such as aheat-exchanging plate 210, and an interface layer 220. In oneembodiment, the heat-exchanging plate 210 is associated with one or morePeltier-type TEC elements supplied with coolant and power from thetreatment unit 106 (FIG. 1).

The heat-exchanging plate 210 can contain a communication component 215that communicates with the controller 114 to provide a first sensorreading 242 as described herein, and a sensor 217 that measures, e.g.,temperature of the heat-exchanging plate 210, heat flux across a surfaceof or plane within the heat-exchanging plate 210. The interface layer220 can be a plate, a film, a covering, a sleeve, a cryoprotectantreservoir or other suitable materials described herein and may serve asthe patient protection device described herein. The interface layer 220is located between the heat-exchanging plate 210 and the skin 230 of asubject 101 (FIG. 1), such as the skin of a patient receiving treatmentvia the treatment system 100 and applicator 104 (FIG. 1). Otherinterface layers may be present.

The interface layer 220 can also contain a similar communicationcomponent 225 that communicates with the controller 114 to provide asecond sensor reading 244 and a sensor 227 that measures, e.g., thetemperature of the interface layer 220, heat flux across a surface of orplane within the interface layer 220 or contact pressure with the skin230 of the patient. For example, one or both of the communicationcomponents 215, 225 can receive and transmit information from thecontroller 114, such as temperature and/or heat flux information asdetermined by one or both of the sensors 217, 227. The sensors 217, 227are configured to measure a parameter of the interface withoutsubstantially impeding heat transfer between the heat-exchanging plate210 and the subject's skin 230. The applicator 200 can also containpower components and other components described with respect to FIG. 1and related applications.

In certain embodiments, the applicator 200 can include a sleeve 250 orliner for contacting the patient's skin 230, for example, to preventdirect contact between the applicator 200 and the patient's skin 230,and thereby reduce the likelihood of cross-contamination betweenpatients, minimize cleaning requirements for the applicator 200, etc.The sleeve 250 can include a first sleeve portion 252 and a secondsleeve portion 254 extending from the first sleeve portion. The firstsleeve portion 252 can contact and/or facilitate the contact of theapplicator 200 with the patient's skin 230, while the second sleeveportion 254 can be an isolation layer extending from the first sleeveportion 252. The second sleeve portion 254 can be constructed fromlatex, rubber, nylon, Kevlar®, or other substantially impermeable orsemi-permeable material. The second sleeve portion 254 can preventcontact between the patient's skin 230 and the heat-exchanging plates210, among other things. Further details regarding a patient protectiondevice may be found in U.S. Patent Publication No. 2008/0077201.

In other embodiments, the applicator 200 can include a belt (not shown)that assists in forming a contact between the applicator 200 (such asvia an interface layer 220) and the patient's skin 230. For example, theapplicator 200 can include retention devices (not shown) coupled to aframe. The retention devices may be rotatably connected to the frame bya plurality of coupling elements that can be, for example, pins, balljoints, bearings, or other type of rotatable joints. Alternatively, theretention devices can be rigidly affixed to the end portions ofheat-exchanging element housings. Further details regarding a suitablebelt device may be found in U.S. Patent Publication No. 2008/0077211.

In further embodiments, the applicator 200 can include a vacuum (notshown) that assists in forming a contact between the applicator 200(such as via the interface layer 220 or sleeve 250) and the patient'sskin 230. For example, the applicator 200 can provide mechanical energyto a treatment region. Imparting mechanical vibratory energy to thepatient's tissue by repeatedly applying and releasing a vacuum to thesubject's tissue, for instance, creates a massage action duringtreatment. Further details regarding a vacuum type device may be foundin U.S. Patent Application Publication No. 2008/0287839.

FIG. 3 is a schematic cross-sectional view of an applicator 300 fornon-invasively removing heat from subcutaneous lipid-rich target areasof the subject 101 (FIG. 1) in accordance with another embodiment of thetechnology. The applicator 300 includes a housing 301 having a vacuumcup 302 with a vacuum port 304 disposed in the vacuum cup 302. Thehousing 301 is coupled to or otherwise supports a first applicator unit310 a on one side of the cup 302, and a second applicator unit 310 b onan opposing side of the cup 302. Each of the first and second applicatorunits 310 a and 310 b can include a heat-exchanging unit (e.g., acooling unit), such as a heat-exchanging plate 312 (shown individuallyas 312 a and 312 b), and an interface layer 314 (shown individually as314 a and 314 b). In one embodiment, the heat-exchanging plate 312 isassociated with one or more Peltier-type TEC elements supplied withcoolant and power from the treatment unit 106 (FIG. 1). As such, theheat-exchanging plates 312 a, 312 b can be similar to theheat-exchanging plate 210 described above with reference to FIG. 2.

The interface layers 314 a and 314 b are adjacent to the heat-exchangingplates 312 a and 312 b, respectively. Similar to the interface layer 220illustrated in FIG. 2, the interface layers 314 a and 314 b can beplates, films, a covering, a sleeve, a cryoprotectant reservoir or othersuitable materials located between the heat-exchanging plates 312 a and312 b and the skin (not shown) of a subject. In one embodiment, theinterface layers 314 a and 314 b can serve as patient protection devicesas described herein. The interface layers 314 a and 314 b can includecommunication components (not shown) and sensors (not shown) similar tothose described with respect to the interface layer 220 of FIG. 2 forcommunicating with the controller 114 (FIG. 1).

In operation, the rim 316 of the vacuum cup 302 is placed against theskin of a subject (not shown) and a vacuum is drawn within the cup 302.The vacuum pulls the tissue of the subject into the cup 302 and coaptsthe target area with the interface layers 314 a and 314 b of thecorresponding first and second applicator units 310 a, 310 b. Onesuitable vacuum cup 302 with cooling units is described in U.S. Pat. No.7,367,341.

The applicator units 310 a and 310 b can be in communication with thecontroller 114, treatment unit 106, energy-generating unit 107, ifpresent, and power supply 110 (FIG. 1) such that the heat-exchangingplates 312 a, 312 b can provide cooling or other energy to the targetregion based on a predetermined or real-time determined treatmentprotocol. For example, the heat-exchanging plates 312 a, 312 b can firstbe cooled to cool the adjacent tissue of the target region to atemperature below 37° C. (e.g., to a temperature in the range of betweenabout −20° C. to about 20° C.). The heat-exchanging plates 312 a, 312 bcan be cooled using Peltier devices, cooling channels (e.g., channelsthrough which a chilled fluid flows), cryogenic fluids, or other similarcooling techniques. In one embodiment, the heat-exchanging plates 312 a,312 b are cooled to a desired treatment temperature (−20° C., −18° C.,−15° C., −10° C., 0° C.) to cool subcutaneous lipid-rich cells. Thelipid-rich cells can be maintained at a sufficiently low temperature todamage or destroy the lipid rich cells.

Referring back to FIGS. 1-3 together and in some examples of the system100, the treatment device or applicator may be used with a substancethat may (a) provide a thermal coupling between the subject's skin andthe heat-exchanging unit(s) or plates to improve heat transfertherebetween; and/or (b) protect biological tissues of a subject fromfreezing damage (e.g., damage due to ice formation). The substance maybe a fluid, e.g., a liquid, a gel, or a paste, which may be hygroscopic,thermally conductive, and biocompatible.

Some embodiments according to the present technology may use acryoprotectant including a freezing point depressant that can assist inpreventing freezing of non-lipid-rich tissue (e.g., dermal and epidermaltissue) during treatment. Suitable cryoprotectants and processes forimplementing cryoprotectants are described herein and incommonly-assigned U.S. Patent Publication No. 2007/0255362. The freezingpoint depressant can be part of a cryoprotectant that may additionallyinclude a thickening agent, a pH buffer, a humectant, a surfactant,and/or other additives and adjuvants as described herein. The freezingpoint depressant may include, for example, propylene glycol (PG),polyethylene glycol (PEG), dimethyl sulfoxide (DMSO), or other suitablealcohol compounds. In a particular embodiment, a cryoprotectant mayinclude about 40% propylene glycol and about 60% water. In otherembodiments, a cryoprotectant may include about 30% propylene glycol,about 30% glycerin (a humectant), and about 40% ethanol. In anotherembodiment, a cryoprotectant may include about 40% propylene glycol,about 0.8% hydroxyethyl cellulose (a thickening agent), and about 59.2%water. In a further embodiment, a cryoprotectant may include about 50%polypropylene glycol, about 40% glycerin, and about 10% ethanol. In yeta further embodiment, the cryoprotectant can include about 30-50% byvolume of one or more freezing point depressants and include about 50%wt./vol. to about 70% wt./vol. of a combination of one or more of athickening agent, a pH buffer, a humectant, a surfactant, and one moreadditives that (a) facilitate permeation of the cryoprotectant into theepidermis and dermis, (b) increase an intracellular concentration ofsolutes of dermal and epidermal cells, (c) form a hypertoniccryoprotectant formulation and/or (d) hydrophilic and/or lipophobicmolecules.

The cryoprotectant may also provide a means of reducing friction at theinterface between the patient's skin and the treatment device orapplicator. This is expected to improve the draw of tissue against theapplicator, thereby providing a more complete and effective treatment.By way of example, in one specific treatment process, an interfacemember is placed directly over the target area of the patient, and theapplicator 104, 200, 300 with a disposable sleeve or liner is placed incontact with the interface member for treatment. The interface membercan be a reservoir containing a desired volume of cryoprotectant. Theinterface member can include, for example, a non-woven cotton fabric padsaturated with the cryoprotectant. Suitable pads include Webril™ padsmanufactured by Covidien of Mansfield, Mass. Further details regardingthe interface member and associated systems and methods are described incommonly-assigned U.S. Patent Publication No. 2010/0280582. In otherembodiments, however, the interface member can include other suitablepads or devices.

Without being bound by theory, it is believed that effective conductivecooling from the treatment device or applicator 104 depends on a numberof factors. Examples of factors that impact heat removal or extractionfrom the skin and related tissue include, for example, the surface areaof the treatment unit, the temperature of the interface member, themechanical energy delivered to the tissue, the distribution ofcryoprotectant, and the extent of non-uniformities in the contactbetween the interface member and the skin.

E. Structures for Sustained and/or Replenishing Release ofCryoprotectant

Several embodiments of the system can include structures for enhancingsustained and/or replenishing release of cryoprotectant to a treatmentsite. In some embodiments, such sustained release structures can beincorporated within the interface member. For example, FIG. 4 is anenlarged schematic cross-sectional view of another applicator 400 inaccordance with another aspect of the present technology. For purposesof illustration, a number of components of the applicator 400 are notshown or described. The applicator 400 includes (a) an interfaceassembly 450 configured to contact the target area, and (b) a coolingunit 405. In this embodiment, the cooling unit 405 is a component of acooling system integrated with the applicator 400. The cooling unit 405can include a plate 440 having a high thermal conductivity, a coolantchamber 442, and one or more Peltier-type thermoelectric elements 444,such as a plurality of individually controlled thermal segments thatcreate a custom spatial cooling profile and/or a time-varying coolingprofile. Each custom treatment profile can include one or more segments,and each segment can include a specified duration, a target temperature,and control parameters for features such as vibration, massage, vacuum,and other treatment modes. Cooling devices having multiple individuallycontrolled heat-exchanging units are described, e.g., in commonlyassigned U.S. Patent Publication No. US 2008/0077211.

A coolant can circulate through the coolant chamber 442 via supply andreturn 108 a and 108 b, respectively, and the thermoelectric elements444 can selectively heat and/or cool relative to the temperature of thecoolant in the coolant chamber 442 to control the temperature overrelatively large areas of the cooling plate 440. Other embodiments ofthe cooling unit 405 do not include the thermoelectric elements 444 suchthat the coolant chamber 442 extends to the plate 440. In either case,the cooling unit 405 provides a heat sink that cools the interfaceassembly 450. In still other embodiments, the cooling unit 405 may havea different arrangement and/or different features.

The interface assembly 450 of the applicator 400 further controls theheat flux through a plurality of smaller zones and delivers a freezingpoint depressant composition (e.g., cryoprotectant) to the target area.In the illustrated embodiment, the interface assembly 450 includes acryoprotectant container 460 that contains a cryoprotectant 490, and aninterface element 470 through which the cryoprotectant 490 can flow. Thereservoir 460 is configured to provide a continuous or at least anapproximately continuous supply of cryoprotectant 490 to the target areaduring treatment. In other embodiments, the cryoprotectant 490 may beapplied directly to an engagement surface of the applicator 400, theskin of the subject 101, or both, in addition to or in lieu of supplyingthe cryoprotectant 490 via the container 460.

The interface element 470 can include a contact member 472 having a backside 473 a in contact with the cryoprotectant 490 and a front side 473 bconfigured to contact the epidermis of the subject and/or an interfacemember on the subject's skin. The contact member 472 can be a flexiblebarrier (e.g., membrane), a mesh, fabric or other suitable materialthrough which the cryoprotectant 490 can flow from the back side 473 ato the front side 473 b. In other embodiments, the contact member 472can be a substantially rigid barrier that is thermally conductive andconfigured to allow the cryoprotectant 490 to pass from the back side473 a to the front side 473 b. A rigid contact member, for example, canbe a plate with holes or a panel made from a porous metal material. Inother embodiments, the interface element 470 can have a differentarrangement and/or include different features.

Referring to FIGS. 1 and 4 together, the treatment unit 106 (FIG. 1) maybe a refrigeration unit, a cooling tower, a thermoelectric chiller orcooler or any other device or cooling unit capable of removing heat froma coolant in addition to or in lieu of the cooling unit 405 (FIG. 4) atthe applicator 400. The treatment unit 106 can be operatively coupled tothe applicator 400 by supply and return fluid lines 108 a and 108 b thatcirculate chilled fluid (e.g., a coolant) through the applicator 400.Alternatively, the treatment unit 106 can circulate warm fluid to theapplicator 400 during periods of warming. Furthermore, one skilled inthe art will recognize that there are a number of other coolingtechnologies that could be used such that the cooling units or coolersof the treatment unit 106 or the applicator 400 need not be limited tothose described herein.

In accordance with other aspects of the present disclosure sustainedand/or replenishing release of freezing point depressant compositions(e.g., cryoprotectant) can be provided by structures separate from or inlieu of the interface member. For example, FIG. 5 is a schematic,cross-sectional view illustrating the treatment device or applicator 200of FIG. 2 and having a cryoprotectant release structure 502 inaccordance with an embodiment of the present technology. Thecryoprotectant release structure 502 can be configured to absorb and/orotherwise hold a freezing point depressant composition (e.g.,cryoprotectant) and release the composition in a time dependent mannerto the skin 230 of the subject and/or the applicator 200. Accordingly,the release structure 502 can be configured to be placed on the skin 230of the subject at the targeted treatment site prior to the placement ofthe applicator 200. In another embodiment, the release structure 200 canbe adhered to the applicator 200 such that it comes in contact with theskin 230 of the subject as the applicator 200 is positioned at thetreatment site.

In some embodiments, the cryoprotectant release structure 502 can beconfigured to continuously or periodically release cryoprotectant. Therelease rate of cryoprotectant can be related to the absorption and/ordispersion rate of the cryoprotectant. In one embodiment, thecryoprotectant release structure 502 can deliver cryoprotectant at agenerally constant rate throughout most or all of the treatment process.In other embodiments, the cryoprotectant release structure 502 canmaintain contact between the subject's skin 230 and the cryoprotectant.The subject's skin 230 can absorb the cryoprotectant to prevent or limitdamage to non-targeted tissue.

The cryoprotectant release structure 502, in some embodiments, cancontinuously deliver cryoprotectant for a duration of time equal to orgreater than about 15 minutes, about 20 minutes, about 30 minutes, 1hour, or 2 hours. The cryoprotectant release structure 502 can bereplaced for longer treatments. In other embodiments, the releasestructure 502 can be configured to be reloadable during treatment sothat, for example, the release structure 502 can continue to delivercryoprotectant for a longer duration of time.

In one embodiment, the release structure 502 can include an absorbentcontaining a bioabsorbable freezing point depressant (e.g., acryoprotectant). The absorbent can be constructed from cotton materialand/or gauze material and the freezing point depressant can be absorbedon and/or therein. In some embodiments, and while the subject is beingtreated, the absorbent can be positioned between the subject's skin 230and a heat-exchanging surface of a treatment device or applicator 200. Aliner or protective sleeve (e.g., sleeve 250) may be positioned betweenthe absorbent and the applicator 200 to shield the applicator and toprovide a sanitary barrier that is, in some embodiments, inexpensive andthus disposable.

In another embodiment, the release structure 502 can be a microporous orgel pad. For example, the freezing point depressant (e.g.,cryoprotectant) can be absorbed or delivered within the microporous orgel pad that is positioned between the subject's skin 230 and aheat-exchanging surface of a treatment device or applicator 200. The gelpad can release the cryoprotectant to the subject's skin either prior toor during treatment. In some embodiments, the microporous gel pad cancontinually release quantities of freezing point depressant over timeand/or during a treatment session. In some embodiments, the freezingpoint depressant can be released at higher concentrations, highervolumes and/or at more controlled rates than by conventional spreadingthe cryoprotectant on the skin 230 of the subject.

In a further embodiment, the release structure 502 can include anadhesive 504 (e.g., tape strips, textile tapes, etc.), such that therelease structure 502 can be releasably retained on the surface of theskin 230 at the treatment site. In one embodiment, the adhesive 504 canbe on a bottom surface of the release structure 502 such that when therelease structure 502 is placed on a surface of the skin 230 at thetreatment site, the release structure 502 is adhered to the skin 230. Inseveral embodiments, the adhesive 504 can prevent slipping or moving ofthe release structure 502 while positioning the applicator 200 and/orduring treatment. In one embodiment, the adhesive 504 can be positionedaround an outside perimeter of the release structure 502 and beconfigured to retain the release structure 502 at the treatment sitewhile preventing cryoprotectant from leaking or spreading to a surfaceof the skin 230 adjacent to but outside of the treatment site.Accordingly, in such embodiments, the cryoprotectant is retained orsealed against the surface of the skin 230 at the treatment site.

In other embodiments, the adhesive 504 can include layers of adhesivematerial that can store freezing point depressant compositions andrelease quantities of freezing point depressant to the surface of theskin 230. Such adhesive layers may include silicone gels, waxes,hydrocarbon resins, terpene-phenol resins, as well as natural andsynthetic resins. In some embodiments, adhesive layers can providecryoprotectant to the surface of the skin 230 at higher volumes and/orat more controlled rates than by conventional means.

Although a noninvasive applicator unit is illustrated and discussed withrespect to FIGS. 2-5, minimally invasive applicators may also beemployed. In such a case, the applicator and patient protection devicemay be integrated. As an example, a cryoprobe and/or electrode that maybe inserted directly into the subcutaneous adipose tissue to cool orfreeze the tissue is an example of such a minimally invasive applicator.Cryoprobes manufactured by, e.g., Endocare, Inc., of Irvine, Calif. aresuitable for such applications. This patent application incorporates byreference U.S. Pat. No. 6,494,844, entitled “DEVICE FOR BIOPSY ANDTREATMENT OF BREAST TUMORS”; U.S. Pat. No. 6,551,255, entitled “DEVICEFOR BIOPSY OF TUMORS”; U.S. Publication No. 2007/0055173, entitled“ROTATIONAL CORE BIOPSY DEVICE WITH LIQUID CRYOGEN ADHESION PROBE”; U.S.Pat. No. 6,789,545, entitled “METHOD AND SYSTEM FOR CRYOABLATINGFIBROADENOMAS”; U.S. Publication No. 2004/0215294, entitled “CRYOTHERAPYPROBE”; U.S. Pat. No. 7,083,612, entitled “CRYOTHERAPY SYSTEM”; and U.S.Publication No. 2005/0261753, entitled “METHODS AND SYSTEMS FORCRYOGENIC COOLING”.

The treatment device or applicator, the cryoprotectant, and/or othercomponents of the treatment system 100 can be included in a kit (notshown) for removing heat from cutaneous or subcutaneous lipid rich cellsof the subject 101. The kit can also include instruction documentationcontaining information regarding how to (a) apply the composition to atarget region and/or a heat-exchanging surface of the treatment deviceor applicator and (b) reduce a temperature of the target region suchthat lipid rich cells in the region are affected while preservingnon-lipid rich cells proximate to the heat-exchanging surface. In otherembodiments, the kit can include pre-treatment and/or post-treatmentcompositions. The kit can further include one or more dermatologicalpre-treatment and/or post-treatment components such as a dermalagitation brush, cleaning solutions and pads, gauze, bandages, etc.

F. Additional Pre-Treatment Methods and Compositions

Prior to the introduction of cooling treatment, the treatment site canbe pretreated to facilitate or enhance cooling of lipid-rich cells,prevent freezing of non-lipid-rich tissue layers and/or facilitateefficacy of freezing point depressant (e.g., cryoprotectant)formulations applied to the skin of the subject at the treatment site.For example, pre-treatment of the treatment site can enhance the effectof a freezing point depressant. In some embodiments, the firstcomposition can be applied to pre-treat the treatment site to facilitatepermeability of the skin to the freezing point depressant.

In operation, one embodiment according to the present technology mayinclude preparing a target area for treatment by topically applying tothe patient's skin a pad, e.g., Webril™ manufactured by Covidien, whichis saturated with thermal coupling fluid such as a cryoprotectant gelincluding a temperature or freezing point depressant. The pad can beplaced at the treatment site for a period of time (e.g., about 1 minuteto about 5 minutes, about 1 minute to about 2 minutes, about 5 minutesto about 10 minutes, less than about 10 minutes, less than about 5minutes, etc.) prior to commencing cooling treatment with a treatmentdevice. In some embodiments, the pad can be at a natural body surfacetemperature (e.g., 30° C.-34° C.), at an internal body temperature(e.g., 37° C.) or warmer prior to positioning the pad at the treatmentsite.

In another embodiment, heat can be applied to the treatment site priorto introduction of cooling treatment for the destruction or alterationof lipid-rich cells. FIG. 6 is a flow diagram illustrating a method 600for pre-treating a target site using heat prior to cooling the targetsite in accordance with an embodiment of the present technology. Eventhough the method 600 is described below with reference to the treatmentsystem 100 of FIG. 1 and the applicators 104, 200, 300 and 400 of FIGS.1, 2, 3 and 4, respectively, the method 600 may also be applied in othertreatment systems with additional or different hardware and/or softwarecomponents.

As shown in FIG. 6, the method 600 can include warming the treatmentsite (block 602) and applying a freezing point depressant (block 604).For example, a surface of a heating element can warm the upper layers(e.g., epidermal and dermal layers) of the treatment site prior toapplying a freezing point depressant (e.g., cryoprotectant).Alternatively, the freezing point depressant can be heated prior toapplying the composition to the treatment site. Without being bound bytheory, it is believed that higher temperatures may potentiallyfacilitate greater cryoprotectant loading, absorption rates, and/orretention in the epidermal and dermal layers above the lipid-rich cellsof the target region. In one embodiment, pre-heating the upper layers ofthe skin (e.g., the non-lipid rich cells) can increase the skinpermeability to freezing point depressant formulations. In someembodiments, warming of the treatment region would facilitate use ofcryoprotectants having higher viscosities (e.g. >10,000 cP) at lowtemperatures (e.g. about 5° C. to about −15° C., 20° C. to about −20°C.). In one embodiment, the epidermis and/or dermis layers can be warmedto a temperature of between about 25° C. to about 45° C., about 25° C.to about 40° C., about 25° C. to about 35° C., about 26° C. to about 30°C., or about 35° C. to about 45° C. (e.g., about 40° C.). In otherembodiments, the surface of the skin can warmed to about 30° C. to about40° C.

In various embodiments, heat can be applied to the treatment site priorto introduction of cooling for a predetermined period of time prior tothe introduction of cooling treatment. For example, heat can be appliedto the treatment site for about 1 minute to about 30 minutes. In anotherembodiment, heat can be applied to the treatment site for about 15minutes, about 20 minutes, about 30 minutes or greater than 30 minutes.

Following warming of the upper layers of the skin, freezing pointdepressant (e.g., cryoprotectant) can be applied topically to the skinof the treatment site by administering a volume of cryoprotectant in aliquid or gel form, for example, directly to the skin. For example,applying the cryoprotectant may include spraying or smearing thecryoprotectant onto the skin using an instrument including, e.g., aspatula, a spray bottle or syringe, or by an operator's gloved hand. Inanother embodiment, a pad having cryoprotectant absorbed therein can beplaced on the skin of the subject at the treatment site.

The method 600 can continue by positioning one or more applicators onthe subject (block 606). For example, surfaces of the applicator unit(s)can couple with the surface of the subject's skin at a target region. Inone embodiment, the applicator unit can include a heat-exchanging unit,a heat-exchanging plate or cooling plate. In another embodiment, thesurface of the applicator unit can be the surface of an interface layeror a patient protection sleeve/liner. Coupling of the surface(s) of theapplicator unit(s) to the surface of the skin can be facilitated byusing restraining means, such as a belt or strap. In other embodiments,a force (e.g., vacuum or suction force) can be used to positively couplethe subject's skin at the target region to the surfaces.

Additionally, the method 600 can also include continually supplyingcryoprotectant to the skin of the subject (block 608). The continuallysupplied cryoprotectant may maintain a sufficient concentration ofabsorbed cryoprotectant in the epidermis and/or dermis of the subject atthe treatment site for reducing the risk of freezing damage. In oneembodiment, a freezing point depressant release structure can bepositioned between a subject's skin and the applicator to facilitatesustained and/or replenishing release of the cryoprotectant to the skinduring a treatment session. The cryoprotectant composition suppliedduring a treatment session can be the same composition or, in otherembodiments, a different composition than the cryoprotectant compositioninitially applied in step 604.

The method 600 can also include removing heat from the target region ofthe subject (e.g., human or animal patient) during a treatment processselectively to cool lipid-rich cells in the target region to atemperature below normal body temperature (block 610). For example, thelipid-rich tissue can be cooled to a temperature below about 37° C.,below about 20° C., below about 10° C. or below about 0° C. such thatlipid-rich cells are affected without substantially affectingnon-lipid-rich cells. In some embodiments, the lipid-rich tissue can becooled to about −20° C. to about 20° C., to about −18° C. to about 5° C.or to about −15° C. to about 0° C.

In further embodiments, methods that facilitate uptake (e.g.,absorption) of cryoprotectant in the dermal and epidermal skin layers(e.g., across the stratum corneum) prior to or during cooling treatmentcan also include applying mechanical stimulation/agitation of the skinat the treatment site prior to introduction of cooling treatment for thedestruction or alteration of lipid-rich cells. FIG. 7 is a flow diagramillustrating a method 700 for pre-treating a target site usingmechanical stimulation of the skin in accordance with an embodiment ofthe present technology. Even though the method 700 is described belowwith reference to the treatment system 100 of FIG. 1 and the applicators104, 200, 300 and 400 of FIGS. 1, 2, 3 and 4, respectively, the method700 may also be applied in other treatment systems with additional ordifferent hardware and/or software components.

As shown in FIG. 7, the method 700 can, optionally, include cleaning atreatment site to remove oil and/or other debris from the surface of theskin at the treatment site (block 702). The method 700 can also includeapplying a freezing point depressant (block 704) to the treatment site.In one embodiment, the freezing point depressant (e.g., cryoprotectant)can be applied topically to the skin of the treatment site byadministering a volume of cryoprotectant in a liquid or gel form, forexample, directly to the skin. For example, applying the cryoprotectantmay include spraying, coating or rubbing the cryoprotectant onto theskin using an instrument including, e.g., a spatula, a spray bottle orsyringe, or by an operator's gloved hand.

The method 700 can continue with mechanically stimulating the skin atthe treatment site (block 706). Mechanical stimulation can include, forexample, stimulation or agitation by brushing, rubbing, ultrasound orother means which can cause the barrier of the stratum corneum (i.e.,the outermost layer of the epidermis consisting of dead cells) to betemporarily reduced and/or increase movement (e.g., turbulence) of thecryoprotectant with respect to the skin. Without being bound by theory,it is believed that mechanical stimulation of the skin (e.g., agitationof, reduction of, or penetration of the stratum corneum) can enhance thepermeation of the cryoprotectant into the underlying epidermal anddermal skin layers. In one embodiment, the skin can be mechanicallystimulated (e.g., abrading, brushing, rubbing, etc.) for about 1 minuteto about 10 minutes. In another embodiment, mechanical stimulation canbe applied to the treatment site for about 1 minute, about 2 minutes,about 5 minutes or greater than 5 minutes. In some embodiments,mechanical stimulation could be performed with, for example, a dermalagitation brush, a brush having rotating bristles, a portion of gauze orthe like. Brushing or rubbing the skin can include, in some embodiments,moving across the skin at the treatment site in a circular motion or inother embodiments, in linear strokes.

In other embodiments, mechanical stimulation can include mechanicalabrasion of the skin that can induce at least mild exfoliation of thestratum corneum thereby enhancing uptake of the topically appliedcryoprotectant. Examples of mechanical abrasion can include vigorousbrushing, scrubbing or other related means for causing exfoliation ofthe skin.

In some embodiments, cryoprotectant could be topically applied followingmechanical stimulation of the skin at the treatment site. In furtherembodiments, aspects of the methods 600 and 700 could be combined toincrease uptake of cryoprotectant prior to cooling the treatment site.For example, heat may be applied prior to administering cryoprotectantand these steps could be followed by mechanical agitation of thetreatment area to further facilitate uptake of the freezing pointdepressant in the epidermal and dermal layers of the skin.

Various aspects of the methods 600 and 700 can include a cosmetictreatment method for treating the target region of a human subject'sbody to achieve a cosmetically beneficial alteration of subcutaneousadipose tissue, a reduction in undesirable sweat secretion, or reductionin sebum secretion. Such a method could be administered by anon-medically trained person.

One expected advantage of several of the embodiments of the methods 600and 700 is that an operator may use lower treatment temperatures forselectively affecting lipid-rich cells of the subject without causingfreezing damage to the dermal and epidermal tissue layers of thesubject. The applied freezing point depressant compositions (e.g.,cryoprotectant) may lower the freezing point of the skin of the subjector body fluid in the target region to at least reduce the risk ofintracellular and/or extracellular ice formation at such low treatmenttemperatures. Additionally, aspects of the methods 600, 700 enhanceloading and/or retention of the cryoprotectant in the epidermal anddermal layers.

Another expected advantage of some of the embodiments of the methods 600and 700 is that the dermis and/or epidermis of the subject may becontinually protected against freezing damage due to the sustainingand/or replenishing administration of cryoprotectant, and/or due to theadministration of longer-lasting cryoprotectant formulations disclosedherein.

Additional aspects of the present technology include pre-treatmentcompositions, which can in some embodiments be a first cryoprotectantcomposition, that can be applied to the skin of the subject prior toapplying a second composition (e.g., a cryoprotectant delivered inconjunction with a system applicator) and initiating cooling treatment.In various embodiments, application of the pre-treatment composition orfirst cryoprotectant composition, to the skin of the subject prior toapplication of a second cryoprotectant composition can facilitate anabsorption of the freezing point depressant in the first and/or secondcryoprotectant compositions. For example, in some embodiments,pre-treatment compositions can enhance skin permeability (e.g., tofacilitate cryoprotectant penetration and distribution within the dermisand epidermis of the treatment site). In one embodiment, thepre-treatment composition can be applied to the skin when the skin is ator above a natural body surface temperature (e.g., 30° C.-34° C.) toenhance skin permeability. In another embodiment, the pre-treatmentcomposition can be pre-warmed and applied to the skin at a temperaturethat is at or above the natural body surface temperature (e.g., 30°C.-34° C.). In one embodiment, a pre-treatment composition can includeglycolic acid or other alpha-hydroxy acids. In another embodiment, apre-treatment composition can contain on or more of: butylene glycol,oleic acid or other fatty acids, d-limonene or related terpenes andterpenoids, N-methyl-2-pyrrolidone, dimethylsulphoxide,1,3-diphenylurea, dodecyl,N,N-dimethyl-aminoacetate, ethanol and otheralcohols, Azone® and derivatives, ethyl acetate and related esters,beta-cyclodextrin or other cyclodextrins, alcohol, and/or isopropylalcohol.

In another embodiment, the pre-treatment composition includes a freezingpoint depressant and, optionally, additional adjuvants, for facilitatingpreservation of non-targeted tissue at the treatment site. For example,the pre-treatment composition can include a freezing point depressant(e.g., propylene glycol) and an alcohol (e.g., isopropyl alcohol). Invarious embodiments, the pre-treatment composition can also include atleast one of a thickening agent, a pH buffer, a humectant and asurfactant, and can further include at least one of (a) an adjuvantconfigured to increase permeation of the freezing point depressantthrough a stratum corneum of the skin, (b) a solute configured toincrease an effective concentration of the solute in an intracellularfluid or an extracellular fluid in the target region, (c) a hydrophilicmolecule, and (d) a lipophobic molecule. In a particular embodiment, thepre-treatment composition includes about 40% propylene glycol, about 30%isopropyl alcohol and about 30% water.

In other embodiments, pre-treatment and/or post-treatment compositionscan be provided to increase actual or a subject's perception of efficacyassociated with a cooling treatment for aesthetic benefit. For example,a pre-treatment or post-treatment composition can include an anesthetic(e.g., benzocaine, lidocaine, butamben, pramoxine, tetracaine),cosmeceuticals (e.g., daucus carota sativa extract, perfluorodecalin,perfluoro-n-octane), skin conditioners (e.g., squalene, dimethicone,divinyldimethicone, silsesquioxane crosspolymer and related compounds),anti-aging pro-collagen elements (e.g., glycolic acid, superoxidedismutase, niacinimide), fragrances, etc. In other embodiments, apre-treatment or post-treatment composition can include menthyl lactateor related compounds that may enhance or promote vasoconstriction and/orimpart a cooling sensation.

In various embodiments, pre-treatment and/or post-treatment compositionscan be used in combination with other aspects of the technologydescribed herein. For example, a pre-treatment composition can beadministered either during or before performing the methods 600 or 700.Likewise, post-treatment compositions can be administered at theconclusion of any treatment for removing heat from a treatment site toselectively affect lipid-rich cells.

In many embodiments, a series of substances can be applied to the targetregion during the course of a treatment. For example, a first substancecan be a pre-treatment composition, second and third substances caninclude a first cryoprotectant applied prior to heat removal from thetarget region and a second cryoprotectant applied to the target region(e.g., in conjunction with the applicator) during the heatremoval/cooling portion of the treatment. A fourth substance can beapplied to the target region following the cooling process. Such asubstance can be a post-treatment formulation. In particular, varioustreatments can include the application of one or more substances appliedin series and/or, in other embodiments, simultaneously, to facilitateprotection of non-targeted tissue and/or for tissue recoverypost-treatment. Each substance can be adapted to (1) enhance thedelivery or effect of a subsequently applied substance, (2) enhance theeffect of cryotherapy, (3) reduce treatment times, and/or (4) reduceadverse effects of cryotherapy. In certain embodiments, the substancesmay include compositions having the same or at least similarformulations. For example, the application of a second substance may besimply the re-application or replenishment of the first substance. Inother embodiments, the substances applied in series may comprisedifferent compositions. In such embodiments, the earlier appliedsubstances may be wiped or cleaned from the surface of the skin at thetreatment site prior to application of the next substance to be appliedin series. In other embodiments, the later-applied substance(s) can beadded to remaining earlier-applied substances at the surface of theskin.

The system 100 (FIG. 1) can be used to perform several pre-treatment andtreatment methods. Although specific examples of methods are describedherein, one skilled in the art is capable of identifying other methodsthat the system could perform. Moreover, the methods described hereincan be altered in various ways. As examples, the order of illustratedlogic may be rearranged, sub-stages may be performed in parallel,illustrated logic may be omitted, other logic may be included, etc.

G. Treatment Examples Example 1 Effect of Pre-Treating a Treatment Sitewith Mechanical Stimulation Prior to Cooling Treatment

This section describes an example of the clinical use of pre-treatingthe skin of a patient at a treatment site with mechanical stimulation inthe presence of topically applied cryoprotectant prior to applyingcooling treatment for affecting subcutaneous lipid-rich cells.Additional embodiments of the present technology may be practiced withfeatures similar to or different than those described with respect tothis example. Among other features of the present technology, thisexample illustrates that mechanical stimulation in the presence ofcryoprotectant prior to cooling treatment may have utility in theprevention of freezing events or damage when cooling subcutaneouslipid-rich tissue for aesthetic or health-related reasons.

Thirteen patients scheduled for abdominoplasty where offered to undergoa CoolSculpting® treatment on abdominal treatment sites. Each patientunderwent two CoolSculpting® treatment sessions having a 60 minute cycletime and a −15° C. applicator temperature set point. The vacuum was setat 60 per typical recommended settings and a standard CoolSculpting® gelpad and liner were used per instructions. Six patients were assigned toa control group and had no pre-treatment performed prior to theCoolSculpting® treatment. Seven patients were pre-treated usingmechanical stimulation prior to the CoolSculpting® treatment. Thepre-treatment protocol included (a) applying 3 cc of cryoprotectantcontaining 100% propylene glycol (PG), (b) manually spreading thecryoprotectant over the surface of the skin using a gloved hand, (c)mildly brushing the cryoprotectant and skin at the treatment site usinga cosmetic brush with rotating bristles for 2 minutes. Following thepre-treatment protocol, pre-treated patients and control patients beganCoolSculpting® treatment with placement of a gel pad over the treatmentsite followed by placement of a vacuum CoolCore® applicator. Freezeevents were detected using a freeze detection algorithm such as thatdescribed in U.S. Pat. No. 8,285,390. The results are as follows:

TABLE 1 Clinical Detection of Freeze Events for AbdominalCoolSculpting ® Patients With and Without Pre-Treatment of MechanicalStimulation Pre-Treatment using 100% PG for 2 minutes Control TotalCycles @ −15° C. 14 12 Freeze Events  0  5 Probability of Freeze Event0% 42%

In the control group of patients, three patients experienced a total offive freeze events at −15° C. The pre-treated group of patients did notexperience any freeze events at −15° C. In a further control group,three patients underwent six cycles of CoolSculpting® treatment with anapplicator temperature of −13° C. and without pre-treatment. No freezeevents occurred at the −13° C. treatment temperature.

The findings suggest that mechanical stimulation of the skin in thepresence of cryoprotectant prior to cooling treatment can facilitatelowering the treatment temperature during the cooling treatment. Withoutbeing bound by theory, it is believed that mechanical stimulationpre-treatment enhances uptake of the cryoprotectant in the tissuesusceptible of freeze events (e.g., the dermal and epidermal skinlayers). It is further believed that lowering the treatment temperatureof the cooling treatment can have one or more advantages such asdecreasing a cycle time while achieving similar benefit, decreasingvariability in treatment results between patients, increasing consistentfreezing of deeper adipose tissue which could provide better treatmentresults.

Example 2 Pre-Treatment of a Treatment Site with a Pre-TreatmentComposition Followed by Cooling Treatment

This section describes an example of the clinical use of pre-treatingthe skin of a patient at a treatment site with a topically appliedpre-treatment composition prior to applying cooling treatment foraffecting targeted cells. Additional embodiments of the presenttechnology may be practiced with features similar to or different thanthose described with respect to this example. Among other features ofthe present technology, this example describes the use oftopically-applied pre-treatment compositions prior to cooling treatment,which may have utility in the prevention of freezing events or damagewhen cooling targeted tissue for aesthetic or health-related reasons.

In this example, and in clinical or other treatment settings, apre-treatment composition is rubbed (e.g., spread, abraded, dispersed,etc.) onto the skin by a clinician for about 30 to about 45 seconds witha mild abrasive cloth (e.g., a non-woven textured cloth wipe). Thepre-treatment composition comprises about 30% isopropyl alcohol and/oran adjuvant for increasing permeability of the skin at the treatmentsite. The pre-treatment composition also comprises about 40% propyleneglycol and about 30% water. The application of the pre-treatmentcomposition in this manner can allow the propylene glycol (e.g.,freezing point depressant) to permeate the skin.

Following application of the pre-treatment composition as described, andwithout removing the pre-treatment composition, the clinician appliesthe system applicator having a liner with cryoprotectant pre-loadedwithin the liner to the surface of the skin at the treatment site.Certain examples may include steps for removing the pre-treatmentcomposition prior to positioning the applicator. The cryoprotectantcomprises about 40% propylene glycol and about 60% water. In otherexamples, the cryoprotectant can be about 50% propylene glycol and about50% water, or about 60% propylene glycol and about 40% water. Followingpositioning of the cryoprotectant-loaded applicator, heat can be removedtransdermally from the target region. The heat removal process can lastapproximately 30 minutes to about 120 minutes. Other time intervals arealso contemplated. In certain instances, the applicator and/orcryoprotectant can be pre-heated (e.g., to about 26° C., greater thanabout 26° C., etc.), for example, to facilitate attachment of the linerto the applicator. Warming of the applicator and/or treatment site mayincrease the cooling treatment time slightly beyond that otherwiseneeded when no preheat is used. Typical cooling treatment times areapproximately 30 minutes to approximately 120 minutes.

Without being bound by theory, it is believed that the clinical use ofpre-treatment compositions enhances uptake of the cryoprotectant in thetissue susceptible of freeze events (e.g., the dermal and epidermal skinlayers). It is further believed that lowering the treatment temperatureof the cooling treatment can have one or more advantages such asdecreasing a cycle time while achieving similar benefit, decreasingvariability in treatment results between patients, increasing consistentfreezing of deeper adipose tissue which could provide better treatmentresults.

H. Suitable Computing Environments

FIG. 8 is a schematic block diagram illustrating subcomponents of acomputing device 800 in accordance with an embodiment of the disclosure.The computing device 800 can include a processor 801, a memory 802(e.g., SRAM, DRAM, flash, or other memory devices), input/output devices803, and/or subsystems and other components 804. The computing device800 can perform any of a wide variety of computing processing, storage,sensing, imaging, and/or other functions. Components of the computingdevice 800 may be housed in a single unit or distributed over multiple,interconnected units (e.g., though a communications network). Thecomponents of the computing device 800 can accordingly include localand/or remote memory storage devices and any of a wide variety ofcomputer-readable media.

As illustrated in FIG. 8, the processor 801 can include a plurality offunctional modules 806, such as software modules, for execution by theprocessor 801. The various implementations of source code (i.e., in aconventional programming language) can be stored on a computer-readablestorage medium or can be embodied on a transmission medium in a carrierwave. The modules 806 of the processor can include an input module 808,a database module 810, a process module 812, an output module 814, and,optionally, a display module 816.

In operation, the input module 808 accepts an operator input 819 via theone or more input devices described above with respect to FIG. 1, andcommunicates the accepted information or selections to other componentsfor further processing. The database module 810 organizes records,including patient records, treatment data sets, treatment profiles andoperating records and other operator activities, and facilitates storingand retrieving of these records to and from a data storage device (e.g.,internal memory 802, an external database, etc.). Any type of databaseorganization can be utilized, including a flat file system, hierarchicaldatabase, relational database, distributed database, etc.

In the illustrated example, the process module 812 can generate controlvariables based on sensor readings 818 from sensors (e.g., thetemperature measurement components 217 and 227 of FIG. 2) and/or otherdata sources, and the output module 814 can communicate operator inputto external computing devices and control variables to the controller114 (FIG. 1). The display module 816 can be configured to convert andtransmit processing parameters, sensor readings 818, output signals 820,input data, treatment profiles and prescribed operational parametersthrough one or more connected display devices, such as a display screen,printer, speaker system, etc. A suitable display module 816 may includea video driver that enables the controller 114 to display the sensorreadings 818 or other status of treatment progression on the outputdevice 120 (FIG. 1).

In various embodiments, the processor 801 can be a standard centralprocessing unit or a secure processor. Secure processors can bespecial-purpose processors (e.g., reduced instruction set processor)that can withstand sophisticated attacks that attempt to extract data orprogramming logic. The secure processors may not have debugging pinsthat enable an external debugger to monitor the secure processor'sexecution or registers. In other embodiments, the system may employ asecure field programmable gate array, a smartcard, or other securedevices.

The memory 802 can be standard memory, secure memory, or a combinationof both memory types. By employing a secure processor and/or securememory, the system can ensure that data and instructions are both highlysecure and sensitive operations such as decryption are shielded fromobservation.

Suitable computing environments and other computing devices and userinterfaces are described in commonly assigned U.S. Pat. No. 8,275,442,entitled “TREATMENT PLANNING SYSTEMS AND METHODS FOR BODY CONTOURINGAPPLICATIONS,” which is incorporated herein in its entirety byreference.

I. Conclusion

Various embodiments of the technology are described above. It will beappreciated that details set forth above are provided to describe theembodiments in a manner sufficient to enable a person skilled in therelevant art to make and use the disclosed embodiments. Several of thedetails and advantages, however, may not be necessary to practice someembodiments. Additionally, some well-known structures or functions maynot be shown or described in detail, so as to avoid unnecessarilyobscuring the relevant description of the various embodiments. Althoughsome embodiments may be within the scope of the technology, they may notbe described in detail with respect to the Figures. Furthermore,features, structures, or characteristics of various embodiments may becombined in any suitable manner. Moreover, one skilled in the art willrecognize that there are a number of other technologies that could beused to perform functions similar to those described above. Whileprocesses or blocks are presented in a given order, alternativeembodiments may perform routines having stages, or employ systems havingblocks, in a different order, and some processes or blocks may bedeleted, moved, added, subdivided, combined, and/or modified. Each ofthese processes or blocks may be implemented in a variety of differentways. Also, while processes or blocks are at times shown as beingperformed in series, these processes or blocks may instead be performedin parallel, or may be performed at different times. The headingsprovided herein are for convenience only and do not interpret the scopeor meaning of the described technology.

The terminology used in the description is intended to be interpreted inits broadest reasonable manner, even though it is being used inconjunction with a detailed description of identified embodiments.

Unless the context clearly requires otherwise, throughout thedescription, the words “comprise,” “comprising,” and the like are to beconstrued in an inclusive sense as opposed to an exclusive or exhaustivesense; that is to say, in a sense of “including, but not limited to.”Words using the singular or plural number also include the plural orsingular number, respectively. Use of the word “or” in reference to alist of two or more items covers all of the following interpretations ofthe word: any of the items in the list, all of the items in the list,and any combination of the items in the list. Furthermore, the phrase“at least one of A, B, and C, etc.” is intended in the sense one havingskill in the art would understand the convention (e.g., “a system havingat least one of A, B, and C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.). In those instanceswhere a convention analogous to “at least one of A, B, or C, etc.” isused, in general such a construction is intended in the sense one havingskill in the art would understand the convention (e.g., “a system havingat least one of A, B, or C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.).

Some of the functional units described herein have been labeled asmodules, in order to more particularly emphasize their implementationindependence. For example, modules (e.g., modules discussed inconnection with FIG. 8) may be implemented in software for execution byvarious types of processors. An identified module of executable codemay, for instance, comprise one or more physical or logical blocks ofcomputer instructions which may, for instance, be organized as anobject, procedure, or function. The identified blocks of computerinstructions need not be physically located together, but may comprisedisparate instructions stored in different locations which, when joinedlogically together, comprise the module and achieve the stated purposefor the module.

A module may also be implemented as a hardware circuit comprising customVLSI circuits or gate arrays, off-the-shelf semiconductors such as logicchips, transistors, or other discrete components. A module may also beimplemented in programmable hardware devices such as field programmablegate arrays, programmable array logic, programmable logic devices or thelike.

A module of executable code may be a single instruction, or manyinstructions, and may even be distributed over several different codesegments, among different programs, and across several memory devices.Similarly, operational data may be identified and illustrated hereinwithin modules, and may be embodied in any suitable form and organizedwithin any suitable type of data structure. The operational data may becollected as a single data set, or may be distributed over differentlocations including over different storage devices, and may exist, atleast partially, merely as electronic signals on a system or network.

Any patents, applications and other references cited herein, areincorporated herein by reference. Aspects of the described technologycan be modified, if necessary, to employ the systems, functions, andconcepts of the various references described above to provide yetfurther embodiments.

These and other changes can be made in light of the above DetailedDescription. While the above description details certain embodiments anddescribes the best mode contemplated, no matter how detailed, variouschanges can be made. Implementation details may vary considerably, whilestill being encompassed by the technology disclosed herein. As notedabove, particular terminology used when describing certain features oraspects of the technology should not be taken to imply that theterminology is being redefined herein to be restricted to any specificcharacteristics, features, or aspects of the technology with which thatterminology is associated.

I/We claim:
 1. A composition for use with a system for transdermalcooling of targeted cells of a subject having skin, the compositioncomprising: a freezing point depressant configured to be applied to theskin of the subject, wherein the freezing point depressant is configuredto lower a freezing point of cells in an epidermal layer and/or a dermallayer of the skin; at least one of a thickening agent, a pH buffer, ahumectant, and a surfactant; and at least one of: an adjuvant configuredto increase permeation of the freezing point depressant through astratum corneum of the skin and into the epidermal and/or dermal layers;a solute configured to increase an effective concentration of the solutein at least one of an intracellular fluid or an extracellular fluid inthe epidermal and/or dermal layers; a hydrophilic molecule; and alipophobic molecule.
 2. The composition of claim 1 wherein the freezingpoint depressant lowers the freezing point of the cells in the epidermaland/or dermal layers to about −20° C. to about −10° C., about −18° C. toabout −10° C., or about −15° C. to about −10° C.
 3. The composition ofclaim 1 wherein the composition includes the adjuvant, and wherein theadjuvant comprises glycolic acid, lactic acid, citric acid, mandelicacid, alcohol, and/or isopropyl alcohol.
 4. The composition of claim 1wherein the composition includes the solute, and wherein the solutecomprises a calcium salt, a potassium salt, a magnesium salt, ammoniumsulphate, acetic acid, glucose, urea, camphor, menthyl lactate, and/ormannose.
 5. The composition of claim 1 wherein the composition includesthe hydrophilic molecule, and wherein the hydrophilic molecule comprisesa surfactant, a gelatin, a hydrogel, and/or glycolic acid.
 6. Thecomposition of claim 1 wherein the composition includes the lipophobicmolecule, and wherein the lipophobic molecule comprises a fluorocarbon.7. The composition of claim 1 wherein the composition further includes acoloring agent, a fragrance, an emulsifier, a stabilizer, and/or ananesthetic agent.
 8. A system for non-invasive, transdermal removal ofheat from lipid-rich cells of a subject's body, comprising: anapplicator having a heat-exchanging element configured to reduce atemperature of a target region beneath the epidermis of the subjectselectively to reduce the temperature of lipid-rich cells in the targetregion from a natural body temperature to a lower temperature in thetarget region; and a first cryoprotectant configured to lower a freezingpoint of non-lipid-rich cells at the target region, the firstcryoprotectant including one or more of an adjuvant configured toincrease absorption of the first cryoprotectant into an epidermal layerand/or dermal layer at the target region, a solute configured to raisean effective concentration of the solute in the epidermal layer and/ordermal layer, a hydrophilic molecule, and a lipophilic molecule; whereinthe first cryoprotectant protects non-lipid rich cells such that thelipid-rich cells in the target region are substantially affected whilenon-lipid rich cells in the target region are not substantially affectedwhen the temperature is reduced.
 9. The system of claim 8 wherein thefirst cryoprotectant has a freezing point in the range of about −40° C.to about 0° C.
 10. The system of claim 8, further comprising acryoprotectant release structure between a surface of the applicator anda skin surface at the target region, the cryoprotectant releasestructure configured to retain and release the first cryoprotectantbetween the surface of the applicator and the skin surface, wherein thefirst cryoprotectant release structure comprises an absorbent material,a microporous pad, and/or an adhesive configured to adhere to the skinsurface, and wherein the adhesive is configured to releasably retain thefirst cryoprotectant release structure at the skin surface at the targetregion.
 11. The system of claim 8, further comprising a secondcryoprotectant, and a cryoprotectant release structure between a surfaceof the applicator and a skin surface at the target region, thecryoprotectant release structure configured to retain and release thesecond cryoprotectant between the surface of the applicator and the skinsurface, wherein the cryoprotectant release structure comprises eitheran absorbent material, a microporous pad, and/or an adhesive configuredto adhere to the skin surface, and wherein the adhesive is configured toreleasably retain the cryoprotectant release structure at the skinsurface at the target region.
 12. The system of claim 11 wherein theadhesive comprises at least one of a silicone gel, a wax, a hydrocarbonresin, a terpene-phenol resin, an natural resin and a synthetic resin.13. The system of claim 11 wherein the cryoprotectant release structureprovides sustained release of the second cryoprotectant to the skinsurface at the lower temperature, and wherein lipid-rich cells in thetarget region are affected at the lower temperature while non-lipid-richcells proximate the cryoprotectant release structure are preserved. 14.A system for removing heat from subcutaneous lipid-rich cells of asubject having skin, comprising: a treatment unit; an applicator havinga cooling unit in communication with the treatment unit; a pre-treatmentcomposition configured to be applied to the skin to increase apermeability of the skin; and a cryoprotectant composition configured tobe applied to the skin to permeate into the skin to lower a freezingpoint of non-lipid-rich cells in the skin.
 15. The system of claim 14wherein the pre-treatment composition comprises an alpha-hydroxy acid,butylene glycol, a fatty acid, d-limonene, a terpene, a terpenoid,N-methyl-2-pyrrolidone, dimethylsulphoxide, 1,3-diphenylurea,dodecyl,N,N-dimethyl-aminoacetate, ethanol, alcohol, Azone®, Azone®derivatives, ethyl acetate, beta-cyclodextrin, alcohol, and/or isopropylalcohol.
 16. The system of claim 14, wherein the pre-treatmentcomposition and the cryoprotectant composition are combined into asingle composition and applied together onto the skin by rubbing thesingle composition into the skin with a mild abrasive cloth.
 17. Thesystem of claim 14, wherein the pre-treatment composition is firstapplied to the skin and thereafter the cryoprotectant composition isapplied to the skin.
 18. A method for affecting a subcutaneous layer ofa human subject's body, the method comprising: applying a cryoprotectantto a surface of skin at a treatment site; prior to removing heat fromthe treatment site, mechanically stimulating an upper layer of skinwithout appreciatively stimulating the subcutaneous layer of skin at thetreatment site to facilitate absorption of the cryoprotectant; andremoving heat from the treatment site of the human subject to coolsubcutaneous lipid-rich cells in the subcutaneous layer to a temperaturebelow normal body temperature.
 19. The method of claim 18, wherein thestep of mechanically stimulating includes abrading an upper layer of theskin.
 20. The method of claim 18, further comprising warming at leastone of the treatment site and the cryoprotectant before removing heatfrom the treatment site.
 21. A method for affecting a target region of ahuman subject's body, the method comprising: applying a cryoprotectantto a surface of skin at a treatment site; prior to removing heat fromthe treatment site, moving the cryoprotectant along the surface of theskin at the treatment site to facilitate absorption of thecryoprotectant; and removing heat from the target region of the humansubject to cool subcutaneous lipid-rich cells in the target region to atemperature below normal body temperature.
 22. The method of claim 21,wherein moving the cryoprotectant along the surface of the skin includesabrading an upper layer of the surface of the skin and mechanicallystimulating the upper layer of the skin without appreciably stimulatingthe subcutaneous layer of the skin at the treatment site to facilitateabsorption of the cryoprotectant.
 23. The method of claim 21, furthercomprising continually supplying cryoprotectant to the surface of theskin at the treatment site during the removal of heat from the targetregion.
 24. The method of claim 21 wherein prior to removing heat, themethod further comprises warming the treatment site to about 25° C. toabout 45° C., about 25° C. to about 40° C., about 25° C. to about 35°C., or about 26° C. to 30° C.